2021 ASCRS Annual Meeting

Authors

Presenting Author
William C. Christie, MD, ABO    Email the author
Authors
Joseph Tauber, MD, Fangqiu Zhang, MS, Eleonora Safyan, PhD, Tudor Tepelus, PhD, Gary Jerkins, MD

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Paper Abstract

Purpose
The GEMINI I phase 3 study evaluated a secondary efficacy endpoint of intermediate vision of AGN-190584 vs. vehicle in participants with presbyopia. Tasks that require intermediate vision are performed at a viewing distance of 20-40 inches. Distance-corrected intermediate visual acuity (DCIVA) measured at 66 cm (~26 inches) was evaluated.

Methods
GEMINI I is a multicenter, double-masked, randomized, vehicle-controlled, phase 3 study. Participants with presbyopia, age 40 to 55 years, received topical AGN-190584 or vehicle once daily, bilaterally, for 30 days. The intent-to-treat population (ITT) included 323 participants. Study visits: screening, Day 1 (baseline), 3, 7, 14, and 30. Photopic, high contrast DCIVA was measured binocularly at 0, 1, 3, 6, 8, and 10 hours at Day 30. LogMar charts were used for DCIVA measurement. AGN-190584 (pilocarpine 1.25%) is an optimized formulation of pilocarpine designed for presbyopia, enhanced with a proprietary vehicle to reduce vision blur and discomfort following topical administration.

Results
The mean (SD) age was 49.6 (3.53) years in the ITT population. A secondary efficacy endpoint of change from baseline in photopic DCIVA letters at Day 30, Hour 3 comparing AGN-190584 and vehicle was met (p<0.05) and this difference was maintained through 10 hours (p<0.05). AGN-190584, increased the depth of focus and had statistical and clinically significant DCIVA improvements of ≥2 line through 10 hours (p<0.05) without loss in distance VA compared to vehicle. AGN-190584 was well-tolerated and had an acceptable safety profile. GEMINI I met its primary endpoint (proportion of participants gaining ≥ 3 lines in mesopic distance corrected near visual acuity (DCNVA) at Day 30, Hour 3, p<0.05).

Conclusion
AGN-190584 met its primary and secondary endpoint of near and intermediate vision improvement, respectively. AGN-190584 was well-tolerated and provides clinically significant improvements in both near and intermediate vision in participants with presbyopia.

Authors

Presenting Author
Majid Moshirfar, MD, FACS    Email the author
Authors
Francis W. Price Jr., MD, Jonathan Stokes, MBA, Xiaomeng Niu, PhD, Elaheh Shirneshan, PhD

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Paper Abstract

Purpose
An optimized formulation of pilocarpine (AGN-190584) was developed as a pharmacologic treatment for presbyopia. In a phase 3 efficacy and safety study, a new Patient Reported Outcome (PRO) instrument, the Near Vision Presbyopia Task-based Questionnaire (NVPTQ), was used to evaluate vision-related reading performance and associated satisfaction.

Methods
In this multicenter, double-masked, 30-day study (NCT03804268; n=323), individuals with presbyopia were randomized to bilateral AGN-190584 or vehicle (placebo) once daily. Secondary efficacy endpoints included mean change from baseline in mesopic NVPTQ Performance (range: 0-5) and Satisfaction (range: 0-4) domain scores on 4 paper-based reading tasks at Day 30 Hour 3. Change from baseline in photopic NVPTQ domain scores were also assessed. Proportion of responders to AGN-190584 (participants achieving individual-level meaningful change thresholds of ≥0.75 and ≥1.00 point improvement from baseline in mesopic Performance and Satisfaction scores, respectively) at Day 30 Hour 3 was assessed.

Results
At Day 30 Hour 3, statistically significant improvements in Performance and Satisfaction domain scores were reported with AGN-190584 versus vehicle under both mesopic and photopic settings: the mean score difference (95% confidence interval [CI]) between groups was 0.8 (0.6, 1.1) and 0.9 (0.6, 1.2) in vision-related reading performance and 0.8 (0.5, 1.1) and 0.8 (0.6, 1.1) in associated satisfaction (P≤.011 for all), respectively. Of the AGN-190584 group, 24.0% (95% CI: 13.0, 34.9) and 26.8% (95% CI: 16.2, 37.5) more individuals reported improvements at individual-level meaningful change thresholds in mesopic Performance and Satisfaction scores, respectively (P<.001), versus vehicle.

Conclusion
PRO efficacy analyses showed significant treatment benefit in patient-centric outcomes in presbyopia. Participants who received AGN-190584 reported greater ability and satisfaction related to near-vision reading versus participants receiving vehicle in mesopic and photopic settings, supporting the role of pharmacologic treatment for this condition.

Authors

Presenting Author
David Wirta, MD    Email the author
Authors
William C. Christie, MD, ABO, Joseph Tauber, MD, Elaheh Shirneshan, PhD, Sungwook Lee, PhD, Joanna Campbell, PhD

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Paper Abstract

Purpose
To report results of the validated Presbyopia Impact and Coping (PICQ) and Presbyopia Patient Satisfaction Questionnaires (PPSQ) in assessing an optimized formulation of pilocarpine (1.25%; AGN-190584) impacts on daily life and use of compensatory coping behaviors, and on treatment satisfaction, respectively, in individuals with presbyopia.

Methods
In this multicenter, double-masked, 30-day study (NCT03804268; n=323), individuals with presbyopia were randomized to bilateral treatment with AGN-190584 or vehicle (placebo) once daily. Secondary efficacy endpoints included mean change from baseline in PICQ Coping (8 item) and Impact (6 item) domain scores (0-4 range, higher scores indicate worse outcomes) evaluating use of presbyopia coping behaviors or impacts on daily life during the past 7 days. Between-group comparison of the PPSQ composite score (0-100 range, higher score indicates better outcome) measuring satisfaction with different aspects of the study medication was also performed. Both outcomes were analyzed at Day 30 Hour 3

Results
Baseline PICQ Coping and Impact scores were generally comparable between treatment groups. At Day 30 Hour 3, mean score differences (95% confidence interval [CI]) between groups for the Coping and Impact domain scores were -0.5 points (-0.6, -0.3) and -0.3 points (-0.4, -0.1), respectively (P=.011 for both versus vehicle) indicating a greater reduction in the use of presbyopia related coping behaviors and related impact in the AGN-190584 group. Between-group PPSQ composite score difference (95% CI) was 19.5 points (14.7, 24.2) (P<.0001 versus vehicle) indicating participants receiving AGN-190584 were significantly more satisfied with different aspects of the study medication.

Conclusion
Efficacy endpoint analyses showed significant improvement in subjective experiences with presbyopia. Participants who received AGN-190584 reported statistically significant reduction in use of coping behaviors and higher satisfaction with different aspects of treatment, versus vehicle, supporting the value of this pharmacologic treatment option.

Authors

Presenting Author
David Wirta, MD    Email the author
Authors
Vincent Restivo, MD, Gregory D. Parkhurst, FACS, MD, Qiang Guo, PhD, Jeff Penzner, PharmD, Haixia Liu, PhD

Paper Abstract

Purpose
The GEMINI I phase 3 study evaluated the efficacy and safety of AGN-190584 vs. vehicle in participants with presbyopia. Distance-corrected near visual acuity (DCNVA), onset, peak and duration of action were evaluated following treatment with AGN-190584 or vehicle in participants with presbyopia on Days 1, 3, 7, 14 and 30.

Methods
GEMINI I is a multicenter, double-masked, randomized, vehicle-controlled, phase 3 study. Participants aged 40 to 55 with presbyopia received topical AGN-190584 or vehicle once daily, bilaterally, for 30 days. AGN-190584 (pilocarpine 1.25%) is an optimized formulation of pilocarpine designed for presbyopia, enhanced with a proprietary vehicle to reduce vision blur and discomfort following topical administration. Mesopic high contrast binocular DCNVA was analyzed at 0, 0.25, 0.5, 1, 3, 6, 8, and 10 hours, from Day 1 to 30. The proportion of individuals gaining 3 lines or more was assessed as the efficacy endpoint.

Results
The mean (SD) age was 49.6 (3.53) years (N = 323). Primary and secondary efficacy endpoints of the proportion of participants gaining ≥ 3 lines in mesopic DCNVA at Day 30, Hour 3 and Hour 6 were both met, with a significantly higher responder rate (RR) of 22.5% (p< 0.0001) at Hour 3 and 9.7% at Hour 6 (p=0.0114) for the AGN-190584 group compared to vehicle. On Day 30, 15 min after AGN-190584 administration, a significantly higher RR of 7.9% (p = 0.0431) was achieved vs. vehicle. Peak effect was achieved at Hour 1 with a significantly higher RR of 25.9% (p<0.0001) vs. vehicle and maintained up to Hour 6. A similar efficacy response was sustained through Day 14 and 30 with no tachyphylaxis.

Conclusion
GEMINI I demonstrated that bilateral, once-daily dosing of AGN-190584 had a rapid onset (15 min) of near vision improvement, with a peak at 1 hour and duration of up to 6 hours after administration. The improvements in near vision were maintained from Day 1 to Day 30.

Authors

Presenting Author
George O. Waring IV, MD, FACS    Email the author
Authors
Francis Price Jr., MD, Majid Moshirfar, MD, FACS, Eleonora Safyan, PhD, Haixia Liu, PhD, Michael R. Robinson, MD

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Paper Abstract

Purpose
To evaluate the safety and efficacy of an optimized formulation of 1.25% pilocarpine (AGN-190584) compared to vehicle in participants with presbyopia. We report the proportion of gaining 3 lines or more in distance-corrected near visual acuity (DCNVA) and achieving functional visual acuity (20/40 or better binocular DCNVA) at day 30, hour 3.

Methods
In this multicenter, double-masked, randomized, vehicle-controlled, phase 3 study participants with presbyopia, age 40 to 55 years, received topical AGN-190584 or vehicle once daily, bilaterally, for 30 days. Study visits included screening, day 1 (baseline), 3, 7, 14, and 30. DCNVA was assessed binocularly in mesopic and photopic conditions. The proportion of participants gaining ≥ 3 lines in DCNVA, achieving 20/40 or better binocular DCNVA, and safety profile were assessed.

Results
In all, 323 participants (88 males, 235 females) were evaluated. Mean (SD) age was 49.6 (3.53) years. The primary efficacy endpoint, proportion of participants gaining 3 lines or more in mesopic DCNVA at day 30, hour 3, was met with a significantly higher responder rate in the AGN-190584 group (22.5%, p < 0.0001) compared with vehicle. No responders had CDVA (corrected distance visual acuity) loss of > 5 letters and AGN-190584 was tolerable and safe. The proportion of participants achieving 20/40 or better photopic binocular DCNVA was significantly higher in the AGN-190584 group (12.6%, p = 0.0171) compared with vehicle.

Conclusion
An optimized formulation of 1.25% pilocarpine with proprietary vehicle applied once a day bilaterally, was found to be statistically superior in efficacy compared to vehicle, safe and well-tolerated. This phase 3 study met its primary endpoint and demonstrated improvement in near and functional vision for 30 days without impairing distance vision.

★ This paper won Best Paper of Session (BPOS) at the 2021 ASCRS Annual Meeting

Authors

Presenting Author
AnnMarie Hipsley, PhD    Email the author
Authors
Griffin Thomas, Laurent Sabatier, MS, James O'Flanagan, MS, Steven Russell, MS, Brad Hall, PhD

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Paper Abstract

Purpose
To create a Finite Element Model (FEM), which incorporates key anatomical structures including the sclera, ciliary muscles, crystalline lens, lens capsule, zonules, and choroid. Use this FEM to simulate accommodation/disaccommodation.

Methods
A 3D FEM model of the eye was constructed based on current literature, and refined with imaging, histology, and scanning electron microscopy information from human cadaver eyes. FEM analysis was performed using Ansys’ Mechanical software on representative 3D models of ocular structures. Various simulations were performed to illustrate biomechanical movements and interactions of lenticular and extralenticular anatomy of accommodation.

Results
The FEM demonstrated the dynamic movements of the ciliary muscle, zonules, lens, sclera, choroid, and vitreous during accommodation at various ages. AVG has demonstrated the change in lens and cornea shapes necessary for human eye accommodation.

Conclusion
By utilizing FEM of the accommodation system, we gain a deeper understanding of the mechanism of presbyopia. This allows for improved opportunity to restore accommodative power and psuedo-accommodation.

Authors

Presenting Author
AnnMarie Hipsley, PhD    Email the author
Authors
Mitchell A. Jackson, MD, ABO, Robert Edward T. Ang, MD, Olga Rozanova, MD, PhD, Brad Hall, PhD

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Paper Abstract

Purpose
To develop an objective measurement tool for tracking presbyopia progress based on age and near visual acuity.

Methods
Subjects were enrolled in an early feasibility study and separated into 4 categories based on disease progression. Patients were over 40 years of age and showed loss of accommodative ability. Visual outcomes were assessed using the Early Diabetic Retinopathy Study (EDTRS) logMAR charts and wavefront aberrometry. Each patient was evaluated multiple times.

Results
We classified patients into 4 stages based on disease progression. Stage I Early Presbyopia (38-42 years): difficulty reading 20/40 (J5) or better at near. Stage II Acute Presbyopia (42-48 years): need reading add to see 20/40 (J5) or better at near. Stage III Chronic Presbyopia (48-55 years): progressive use of 0.25 D reading ad every year. Stage IV Stable Presbyopia (55+ years): inability to read 20/100 (J10) without reading add. These stages had good correlation with the stages in dysfunctional lens syndrome (DLS).

Conclusion
There is clinical value to classify the prevalence & incidence of age-related ocular decline with the progression of presbyopia. We developed an objective measurement tool for tracking presbyopia progress based on age and near visual acuity. This novel classification system has the potential for stage related treatment intervention.

Authors

Presenting Author
William F. Wiley, MD    Email the author
Authors
Joseph J Ling, MD, Andrew K Yazji, BSc, Shamik Bafna, MD, Kayla L. Karpuk, OD

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Paper Abstract

Purpose
To evaluate the targeted refractive outcomes and visual outcomes achieved after implantation and adjustment of the Light Adjustable Lens (LAL, RxSight) after cataract surgery.

Methods
In this retrospective case series, 148 patients (n=148) who underwent cataract extraction with implantation of the LAL were included. Patients were separated into those with near (calculated preoperatively and after final light adjustment) or distance (plano) refractive targets. Primary outcome measures included best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), mean manifest refraction spherical equivalent (MRSE), and the number of patients within ±0.5D and ±1.0D of refractive target. Data was collected preoperatively, at each adjustment with light delivery device (LDD), after final lock-in with LDD, 1-month post-operatively, and 3-months post-operatively.

Results
148 patients were included in this study (n=148) with 240 eyes. At 3-month follow-up for distance UCVA, 55.8% saw 20/20 or better, 94.8% saw 20/40 or better, & 98.7% saw 20/70 or better. Average MRSE for distance target eyes was -0.354 ± 0.724 D, deviating on average -0.217 ± 0.595 D from target. 73.4% of patients were within ±0.5 D of refractive target and 90.6% were within ±1.0 D. At 3-month follow-up for near UCVA, 51.4% saw 20/20 or better, 83.8% saw 20/40 or better, and 100% saw 20/80 or better. Average MRSE for near target eyes was -1.349 ± 1.021 D, deviating on average -0.072 ± 0.893 D from target. 63.2% of patients were within ±0.5 D of refractive target and 92.1% were within ±1.0 D.

Conclusion
The light adjustable lens provides a high degree of control over the post-operative refractive outcome. It has achieved favorable outcomes in a majority of patients in both distance and near target groups. In patients with irregular corneas, such as radial keratectomy, the light adjustable lens can provide more reliable outcomes.

Authors

Presenting Author
Jay S. Pepose, MD, PhD, ABO    Email the author
Authors
Mina P. Sooch, BEng, MBA, Konstantinos Charizanis, PhD, MBA, Alan R. Meyer, MBA, BEng, Charles b Slonim, MD, Eliot Lazar, MD

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Paper Abstract

Purpose
The objective of this study is to evaluate the efficacy of a kit combination of Nyxol, or 0.75% phentolamine ophthalmic solution (POS), and low-dose pilocarpine for the temporary treatment of presbyopia. POS has shown in multiple Phase 2 trials a tolerable safety profile, significant reductions of pupil diameter, and improvements in near vision

Methods
The VEGA-1 study is a Phase 2, multi-center, randomized, placebo-controlled, double-masked clinical trial. Subjects with distance-corrected near visual acuity (DCNVA) of 20/50 or worse will be randomized to receive either 0.75% POS or placebo vehicle with and without low-dose pilocarpine. The primary endpoint will be the percent of patients with at least 15 letters ETDRS (3 lines) or more of binocular DCNVA improvement relative to baseline on a standard near vision eye chart without loss of distance vision. Trial start-up activities are underway with first patient expected in 1Q21

Results
Enrollment for the VEGA-1 study completed in May 2021 with 150 subjects enrolled across 17 sites. The primary endpoint will be the percent of patients with at least 15 letters ETDRS (3 lines) or more of binocular photopic DCNVA improvement relative to baseline on a standard near vision eye chart at 1 hour. Additional secondary endpoints include near/distance/intermediate visual acuity at multiple timepoints, effect of iris color, percentage of subjects with < 5 letters of loss in distance visual acuity and measurements in pupil diameter over time. Following data lock, topline efficacy and safety data will be analyzed and presented at the meeting.

Conclusion
The results from this Phase 2 trial will define the clinical efficacy and safety profile of a kit combination of 0.75% POS and low-dose pilocarpine for further Phase 3 trials. This approach of POS and LDP may offer a potential new pharmacologic drop option for the treatment of presbyopia.

Authors

Presenting Author
Maria S. Romero, MD, ABO    Email the author

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Paper Abstract

Purpose
To evaluate the need of a validated protocol when using fMRI in the setting of dysphotopsia after cataract surgery

Methods
Settings: PubMed and Research Gate literature review Three publications utilizing fMRI to characterize neuroadaptation after intraocular lens implantation during cataract surgery where identified using appropriate search terms (fMRI, intraocular lens, dysphotopsia, etc) (1-3). These studies where then analyzed to identify common features and differences, with a focus on the sensory input used, patient characteristics, and statistical analysis of the fMRI imaging.

Results
All of the articles showed a positive correlation between patient reported glare and fMRI BOLD signal response. Miranda et al. showed that the population receptive field (pRF) size was inversely correlated to the optical properties of the eye. The papers differed in clear discussions of the size of stimulus used, optimization and validation of the fMRI sequence and/or software used (4,5), and most importantly the statistical techniques used including sensitivity studies of cluster sizes, addressing the false discovery rate, and time-scale analysis of the BOLD signals observed. Additionally, no constraints or sensitivity studies of lobar or cortical activation regions were applied.

Conclusion
The need of a validated protocol to evaluate the role of fMRI to assess neuroadaptation in the settings of dysphotopsia that establishes specific cortex areas to evaluate, standardized visual stimuli, fMRI sequences and software, statistical analysis with cluster size variation, and BOLD signal temporal analysis is needed for future efforts.

Authors

Presenting Author
Robert Edward T. Ang, MD    Email the author
Authors
AnnMarie Hipsley, PhD, Mitchell A. Jackson, MD, ABO, Brad Hall, PhD

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Paper Abstract

Purpose
To evaluate visual benefit of Laser Scleral Microporation (LSM) in presbyopic eyes.

Methods
Scleral microporations were created in critical zones in four quadrants using an Er:YAG laser to improve pliability & biomechanical efficiency of the accommodative apparatus for 22 patients. Patients were over 40 years of age with demonstrated loss of accommodative abilty. Visual outcomes were assessed using the Early Diabetic Retinopathy Study (EDTRS) logMAR charts with and without correction at distance, 60cm and 40cm.

Results
LSM provided improved uncorrected monocular UDVA, UIVA, UNVA from 0.02, 0.20 and 0.43 preoperatively to -0.02, 0.02 and 0.203 at 6 months respectively postoperatively. Distance corrected intermediate and near visual acuity (DCIVA, DCNVA) improved from 0.18 and 0.46 to 0.00 and 0.19 respectively postoperatively with no reduction in distance vision. Spherical equivalent of the manifest refraction was not significantly different from 0.18D (SD 0.27D) preoperatively to 0.21D (SD 0.27) six months postoperatively. Refractive power required to read letters at the logMAR 0.00 level dropped from 2.03D (mean) to 1.15D (mean) at 6 months post-operatively.

Conclusion
Early clinical trial results suggest LSM to be a safe and effective procedure for restoring range of visual performance in presbyopes. Early results also suggest that LSM can improve intermediate and near visual acuity without touching the visual axis and without comprising distance vision. Data collection is ongoing.

Authors

Presenting Author
Cathleen M. McCabe, MD    Email the author
Authors
Aldo A. Martinez, PhD

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Paper Abstract

Purpose
AcrySof® IQ Vivity Extended Vision (model DFT015) is a novel presbyopia-correcting IOL with a non-diffractive design, intended to provide an extended range of vision with a visual disturbance profile similar to a monofocal. We evaluated the visual and safety outcomes of DFT015 compared with a premium aspheric monofocal IOL (model SN60WF).

Methods
This was a prospective, multicenter (11 sites in the US), randomized, parallel-group, confirmatory trial of cataract patients bilaterally implanted with DFT015 (n=107) or SN60WF (n=111). Co-primary and secondary effectiveness objectives for DFT015 compared with SN60WF at Month 6 were to demonstrate superiority in mean photopic monocular distance-corrected intermediate visual acuity (DCIVA; 66 cm) and distance-corrected near VA (DCNVA, 40 cm), non-inferiority in mean photopic monocular best-corrected distance VA (BCDVA; 4 m), and a greater range of defocus at 0.2 logMAR in first eyes. The validated Questionnaire for Visual Disturbances (QUVID) recorded patient-reported visual disturbances.

Results
At Month 6 postoperatively, superiority of DFT015 to SN60WF in mean photopic monocular DCIVA (difference of –0.164 logMAR; p<0.001) and DCNVA (difference of –0.156 logMAR; p<0.001), and non-inferiority in mean photopic monocular BCDVA (95% upper confidence limit of the difference was <0.1 logMAR margin), were demonstrated. DFT015 showed a greater range of monocular defocus compared with SN60WF (difference of 0.54 D at 0.2 logMAR). The frequency of “severe” visual disturbances was low for both groups (DFT015, ≤3.8%; SN60WF, ≤2.7%) Most patients in both groups reported never being bothered by starbursts, halos, or glare (DFT015, ≥73.6%, SN60WF ≥71.8%).

Conclusion
This large, multicenter, randomized study demonstrated that, compared with a premium aspheric monofocal IOL, the novel non-diffractive presbyopia-correcting IOL DFT015 provides superior distance-corrected intermediate and near vision, a greater range of vision, and non-inferior distance vision with a similar visual disturbance profile.