Lynda Charters



The Port Delivery System (PDS) with ranibizumab ( (Lucentis, Genentech, Inc.) met the primary endpoint of the Archway Trial of equivalency and reduced treatment burden when compared with monthly ranibizumab injections, the gold standard, for treating neovascular age-related macular degeneration (AMD).

“Patients with neovascular AMD are often undertreated clinically, leading to suboptimal outcomes, according to Peter Campochiaro, MD, presenting during the American Society of Retina Specialists 2020 Virtual Annual Meeting. “More durable treatments are needed, and the PDS with ranibizumab is an innovation solution for these patients.”

The PDS, an investigational drug delivery system, provides continuous delivery of a customized formulation of ranibizumab; it is a permanent intraocular reservoir that can be refilled during an in-office procedure. 

Ranibizumab is slowly released into the vitreous cavity following implantation at the pars plana.

Campochiaro recounted that the phase 2 Ladder trial of the PDS (100 mg/mL) for neovascular AMD found that the visual and anatomic outcomes were comparable to those obtained with monthly ranibizumab 0.5-mg injections. 

The PDS did not need to be refilled for about 24 weeks or longer in 80% of patients. These favorable results supported the device’s evaluation in the Archway phase 3 trial.

The ongoing trial includes patients (n = 415) with neovascular AMD who had been responsive to any anti-vascular endothelial growth factor therapy. 

The patients were randomized 3:2 to the PDS with ranibizumab (100 mg/mL) doses every 24 weeks (248 patients) or monthly intravitreal injections of ranibizumab 0.5 mg (167 patients), with the goal of evaluating the noninferiority and equivalency of the PDS compared with the injections.

The primary endpoint was the change in the best-corrected visual acuity (BCVA) compared with baseline averaged over weeks 36 and 40. If disease activity became apparent in the PDS group during the study course, patients could receive supplemental injections of ranibizumab.

The baseline BCVA was 20/32 in both groups following a mean of 5 anti-VEGF injections before baseline. The study had a 98% retention rate at the primary analysis.

Campochiaro reported that the Archway Study met the primary endpoint, i.e., the PDS with every-24-week dosing was noninferior and equivalent to monthly ranibizumab. 

“Compared with the gain in 0.5 letter in the monthly injection arm, the gain of 0.2 letter in the PDS arm was noninferior and equivalent to the protocol-specified margin for each of 4.5 letter,” he commented.

A transient reduction in the BCVA was seen in the PDS arm that was related to the implantation procedure. The BCVA returned to the baseline value by week 12.

“The excellent baseline BCVA from previous treatment was well maintained in each study arm,” he said. In line with this, the normal baseline center point thickness was maintained through week 40 in the PDS arm, similar to the injection arm.

The vast majority of patients in the PDS group (98%) did not require supplemental treatment during the first refill-exchange interval.

“To week 40, the total number of treatments, i.e., implantation, refills, or supplemental injections, was 2 in the PDS arm compared with 10.7 injections in the monthly ranibizumab arm,” he said.

The device implant and refill-exchange procedures were generally well tolerated, but there were some adverse events of special interest. 

In the PDS arm, the adverse event that occurred most often was a nonserious conjunctival bleb in 6.5% of patients; vitreous hemorrhages occurred in 5.2% and resolved spontaneously; no traumatic cataracts developed; conjunctival retraction/erosion occurred in 4.4%. 

Four cases (1.4%) of endophthalmitis developed that were related to the conjunctival retraction; in 1 case the visual loss was irreversible and in 3 cases the vision returned to the baseline level. Two retinal detachments occurred that required surgery. 

The device dislocated in 1 case into the vitreous cavity during a refill-exchange procedure; the device was removed and the vision returned to baseline.

The major take-home points are the following. The trial showed that the PDS met the primary endpoint of equivalency and reduced treatment burden compared with monthly ranibizumab. 

The combination of surgery, device, and drug was generally well tolerated with a favorable benefit/risk profile.

“Since ranibizumab was approved in 2006, new treatments have provided incremental benefits,” Campochiaro concluded. “The PDS is the first new treatment that provides a paradigm shift in the management of neovascular AMD.”


Dr. Campochiaro is on the advisory board of Genentech and is an investigator for and received grant support and honoraria from Genentech. He is lead author of this study, and professor of ophthalmology, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 

Articles

PDS with ranibizumab is proving to be an innovation solution for nAMD patients. Peter Campochiaro, MD, detailed findings of phase 2 of the Ladder Trial and ongoing Archway Trial during the virtual 2020 ASRS annual meeting.

ASRS 2020: PDS with ranibizumab signals paradigm shift in treatment of neovascular AMD



The results of the Protocol T Extension Study to assess treatment of center-involved diabetic macular edema (DME) with anti-vascular endothelial growth factor (VEGF) therapy showed visual acuity (VA) declines over the 3-year period after the end of the Protocol T study.

While the final VA at the 5-year time point remained above that achieved at the end of the Protocol T study, the results emphasized the need for methods to maintain the initial VA increases achieved.

Dante Pieramici, MD, reported the results of the Protocol T Extension Study on behalf of the DRCR Retina Network during the virtual 2020 American Society of Retina Specialists 2020 Virtual (ASRS) meeting.

Protocol T was a 2-year multicenter clinical trial in which aflibercept (Eylea, Regeneron Pharmaceuticals), bevacizumab (Avastin, Genentech, Inc.) and ranibizumab (Lucentis, Genentech, Inc.) were compared for treating DME in 660 eyes in which the baseline VAs ranged from 20/32 to 20/320. 

All patients had center-involved DME and had received no or minimal treatment for the DME, Dr. Pieramici recounted.


In the extension study, the eligible patients were assessed during a 5-year visit, i.e., 3 year after the end of Protocol T. At the 5-year visit, the VA was measured, optical coherence tomography images and color photographs were obtained, and patients were examined.

“The primary objective of the extension study was to obtain additional information about the 3 years after the end of Protocol T to gain insight into the treatment course and follow up on the VA and DME in years 2 to 5. 

The main outcome was not to compare the treatments groups after 2 years because the patients had been managed at physician discretion during that time,” he said.

A total of 317 patients were eligible to participate in the extension study. Of these, 95% of the participants had undergone 1 or more retinal examinations (mean, about 14) since the end of Protocol T.

During the 2- to 5-year period, 70% of patients were treated 1 or more times for DME or diabetic retinopathy, most of which were anti-VEGF drugs (median number of injections, 4 in about 67% of patients); small percentages of patients were treated with corticosteroids, focal or grid laser, or panretinal photocoagulation, Dr. Pieramici reported.

About a third of patients did not receive additional VEGF injections during the period of the extension study, and about 10% received 20 or more injections during the evaluated time period.

“At the end of the extension study, the VA decreased to an average of +7.4 letters compared with the Protocol T increase of +12.2 letters in all treatment groups, for a mean decrease of about 1 line of VA, Pieramici said. “However, this level was still better than the baseline VA. When the effects of anti-VEGF treatments were analyzed, the same downward trajectory was seen for the 3 drugs.”

When the VA was analyzed according to the baseline VAs, the same pattern of results was seen. 

However, despite the VA decline over the 3-year period, almost 50% of the patients had 20/25 or better VA at the 5-year time point and 75% had 20/40 or better VA.

The mean central subfield thickness changed very little between years 2 and 5, -156 µ versus -154 µ, respectively. 

This also was the case when the groups were analyzed based on the original treatments. At 5 years, only about one-third of patients had some measurable DME.

Based on the results of the Protocol T Extension Study, the takeaway points were as follows:

 The patients received standard care after Protocol T concluded. That is, 95% of patients received retinal care and 68% had at least 1 injection of an anti-VEGF drug. On average, the patients maintained VA gains from baseline, but the mean VA decreased from years 2 to 5, and the central subfield thickness did not change significantly during those years.

 The results of the Protocol T Extension Study differed from previous studies of DME that reported sustained VA increases, as in the Protocol I study.

 Strategies are needed to improve the long-term VA outcomes in the clinical care of eyes with DME.

Dr. Pieramici is a consultant to and receives research funding from Genentech, Inc. and Regeneron Pharmaceuticals. He is in private practice in Santa Barbara, California. 

The results of the Protocol T Extension Study underscore the need for methods to improve long-term visual gains in eyes with diabetic macular edema, according to Dante Pieramici, MD, on behalf of the DRCR Retina Network, during the American Society of Retina Specialists 2020 Virtual Annual Meeting. 

ASRS 2020: Protocol T Extension Study shows long-term visual declines in DME eyes

), when tested at extended dosing intervals of every 16 weeks and every 12 weeks, provided sustained anatomic and visual outcomes comparable to those achieved with ranibizumab (Lucentis, 

The phase 2 Stairway Trial showed that the drug blocked angiopoietin 2 (Ang-2) and vascular endothelial growth factor (VEGF), both of which synergistically drive vascular instability, characterized by vascular leakage, neovascularization, and inflammation in retinal diseases such as age-related macular degeneration (AMD), according to Carl Danzig, MD, who presented results of the trial during the virtual 2020 American Society of Retina Specialists annual meeting.

Faricimab is the first bispecific antibody designed for intraocular use and can simultaneously bind and neutralize Ang-2 and VEGF-A. 

He explained that the bispecific antibody has 2 Fab arms in a specifically engineered Fc region: Anti-Ang-2 Fab stabilizes and protects vessels and anti-VEGF-A Fab inhibits vascular leakage and neovascularization.

The phase 2 multicenter, randomized, controlled clinical study evaluated the extended durability of faricimab for treating neovascular AMD. 

Specifically, the investigators assessed the effects of every-16-week flex doses or every-12-week doses of faricimab compared with monthly ranibizumab. All patients treated with faricimab first received 4 doses administered every 4 weeks through week 12 (loading dose) followed by a 12-week period with no treatment. 

At week 24, the disease activity was assessed, including measurement of the central subfield thickness and BCVA, presence of macular hemorrhages, and the investigators’ opinions. 

The primary efficacy objective was the change in the best-corrected visual acuity (BCVA) from baseline.

The patients randomized to the every-16-week flex dosing who had active disease at 24 weeks went on to every-12-week dosing. Those without active disease were eligible for every-16-week dosing.

“Overall, 65%, that is, 36 of 55 patients treated with faricimab were free of disease activity at week 24; 19 of 31 patients in the every-16-week flex group had no disease activity at week 24 and were treated at every-16-week intervals to week 52,” Danzig said. “All other patients were treated with every-12-week dosing.”

Measurements of the BCVA showed that the gains in vision achieved with the every-16-week flex dosing and every-12-week dosing were maintained at week 52 and were comparable to those seen with monthly ranibizumab (+11.42, +10.08, and +9.59 letters, respectively).

Improvements in BCVA, central subfield thickness, choroidal neovascularization lesion size, and area of leakage with faricimab dosed every-16-week flex and every 12 weeks were comparable to those achieved with monthly ranibizumab.

According to Danzig, the main take-home points of the study include Ang-2 and VEGF-A are key drivers of vascular instability characterized by vascular leakage, neovascularization, and inflammation. Faricimab is the first bispecific antibody designed to simultaneously inhibit Ang-2 and VEGF-A.

The Stairway trial showed that the initial BCVA gains were meaningful and fully maintained through week 52 with every-16-week flex and every-12-week dosing arms. 

No active disease was seen in 65% of all patients treated with faricimab 12 weeks after the last loading dose and were eligible for every-16-week dosing. Anatomic improvements were comparable between faricimab and ranibizumab.

According to Danzig, based on the Stairway trial results, 2 large phase 3 studies, Tenaya and Lucerne, are assessing the efficacy, safety, and durability of faricimab in patients with neovascular AMD. The drug is also under investigation in phase 3 clinical trials to treat diabetic macular edema.

Dr Danzig is a consultant to Genentech Inc. He is is in private practice at the Rand Eye Institute, Pompano Beach, Florida.

Carl Danzig, MD, presented results of phase 2 Stairway Trial during the virtual 2020 American Society of Retina Specialists (ASRS) annual meeting. 

ASRS 2020: Trial shows faricimab blocks Ang-2 and VEGF-A 

An augmented-reality (AR) headset (Oculenz, Ocutrx) enhances functional vision in patients with severe age-related macular degeneration (AMD). 

The device de-emphasizes the patient’s scotoma, enhances letter reading, and improves face recognition.

AR enhances the real world in contrast to virtual reality, which replaces the real world. AR is ideal for complete user freedom, use in high and low light, and for applications in low vision, medicine, and education, Linda Lam, MD, MBA, explained.

Lam detailed the AR headset during a presentation at the American Society of Retina Specialists 2020 virtual annual meeting.

Considered the huge number of patients who currently have AMD and the exponential growth of that number over the next few decades, there is a dearth of products that can help this patient population. 

Regarding devices, only virtual reality and not AR devices are available; and those that are available are inconvenient to use in that they are heavy or tethered, can be used indoors only, provide no peripheral vision, patients cannot walk with the devices, and none move images outside of the scotoma, she commented.

In contrast, the headset is a novel AR device specifically designed for low-vision or visually impaired patients. 

The device weighs less than a cell phone, provides the highest resolution visible to the eye (60 pixels/degree), has a 120-degree field of view, and contains eye-tracking technology.


First, the patient wears the headset and takes a visual field test, during which the patient sees concentric circles and light streaks. The device then maps the areas in the patient’s vision that are blocked by the scotoma with a scotoma marker.

“The key point with this device is that the unique scotoma marker in the software matches the patient’s scotoma in each eye,” Lam said.


During this process, the scotoma marker data are stored in the device’s processing unit and the video from the 4K cameras at the top of the device are taken from the real world. 

The Oculenz technology moves the images outside of the scotoma while the micro-display projects a hybrid image onto the lens.


Infrared lights in the device illuminate the eye gaze, which allows the eye-tracking cameras to follow the eye movements. Lam explained that the eye-tracking keeps the scotoma marker in line with the augmented image on the lens.

Step 4: image is moved to healthy retina. 


She demonstrated that the device shifts elements of the image from the scotomatous area that is not visible to the patient to healthy retina to facilitate the wearer’s view.

 
The visual field test results can be sent to physicians from the patient’s home and cut down on office visits. 

The device also can send alerts to the physician if the device perceives changes in the scotoma, which may indicate AMD progression.

Lam demonstrated use of a previous generation of the Oculenz that did not have the eye-tracking feature or provide magnification.

She reported that the patient’s vision improved by 4 lines and he was able to recognize his wife for the first time in years. He completed reading through the 4th line down on the Snellen chart.

Using that previous iteration of the device, the results indicated that in 5 patients (10 eyes) the average improvement was 17 to 19 letters (range, 5 to 34 letters).

The Simultaneous Localization and Mapping software provides instant location mapping and object identification of 7 million objects recognized and guides patients through their surroundings. 

For example, in a patient with AMD who also has glaucoma with loss of peripheral vision, the Oculenz tells the patient “Stop. There is a curve 2 feet to your left” or “Stop. There is a chair 4 feet to your right.”

Lam concluded that Oculenz is a novel AR device specifically developed for patients with low vision and visual impairment.

“ It is the lightest weight device on the AR market, weighing only 250 grams, has the highest resolution, widest field of view, and has patented eye-tracking technology,” she said. “It also has a feature called dynamic opacity, which senses the surrounding ambient light; is wireless; and has artificial intelligence and machine learning voice command and control.”

The device is expected to be commercially available in early 2021.

Dr. Lam is a consultant to Ocutrx. She is an associate professor of ophthalmology, USC Keck School of Medicine, Los Angeles.

An augmented-reality device provides AMD patients with enhanced reading ability and facial recognition.

Author | Lynda Charters

Articles

ASRS 2020: PDS with ranibizumab signals paradigm shift in treatment of neovascular AMD

ASRS 2020: Protocol T Extension Study shows long-term visual declines in DME eyes

ASRS 2020: Trial shows faricimab blocks Ang-2 and VEGF-A

ASRS 2020: Augmented-reality headset provides vision for AMD patients