Ocular Adverse Events Research Articles

Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study

Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to anti-VEGF were assigned to four cohorts differing by ixo-vec dose (2×1011 vs 6×1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6×1011 dose group and in 7 participants in the 2×1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2×1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2×1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6×1011 vg/eye cohorts. Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions. Adverum Biotechnologies.

Rates of Ocular Adverse Events after Intravitreal Faricimab Injections

Based on one-year experience with faricimab in a large retina-only practice, our study identified a 1.9% rate of serious ocular adverse events and a similarly low rate of intraocular inflammation that was comparable to clinical trials.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice

PurposeTo describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in routine clinical practice. VOYAGER also aims to understand drivers of real-word treatment outcomes by gaining novel insight into the intersection of treatment regimens, treatment decisions, anatomic outcomes and vision. DesignPrimary data collection, noninterventional, prospective, multinational, multicenter real-world study. ParticipantsAt least 5000 patients initiating or continuing faricimab or PDS for nAMD or DME across 500 sites in 31 countries. MethodsManagement will be per usual care, with no mandated schedule visits or imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomical features and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome MeasuresThe primary endpoint is VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary endpoints include VA change over time and according to treatment regimens (fixed, treat-and-extend, pro re nata, other) and number. Exploratory endpoints include VA change in relation to presence/location of anatomical features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, disorganization of retinal inner layers) and according to treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety (ocular and nonocular adverse events). ResultsRecruitment commenced in November 2022 and will continue until late 2027 allowing for up to 5-years of follow-up. Exploratory interim analyses are planned annually. ConclusionsVOYAGER is an innovative real-world study of retinal diseases that will assess effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes for patients.

Ocular Surface Adverse Events are not Associated with Dupilumab use in Nasal Polyp Treatment.

Ocular surface reactions (OSR) have been associated with dupilumab for atopic dermatitis (AD) treatment. However, the association of dupilumab-associated OSR (DA-OSR) for nasal polyps (CRSwNP) treatment has not been studied. We evaluated DA-OSR for CRSwNP treatment using the FDA Adverse Event Reporting System (FAERS). FAERS was queried for any general ocular reactions (DA-GOR) from 2019Q1 to 2022Q4. DA-OSR were subcategorized from DA-GOR and compared between treatment groups (CRSwNP, asthma, AD). Logistic regression was used to predict DA-OSR. Disproportionality analysis (DPA) of DA-OSR was performed using OpenVigil. There were 60,198 total observations, of which 5344 were treated for CRSwNP. The prevalence of DA-GOR and DA-OSR was greatest for AD (15.3%, 7.8%), followed by CRSwNP (12.2%, 6.7%) and asthma (9.2%, 3.5%). The most commonly reported OSRs were dry eyes (35.9%), conjunctivitis (15.7%), and increased lacrimation (11.0%). The reported odds ratio (ROR) of CRSwNP-treated DA-OSR was 0.84 (0.73-0.97; p = 0.015), compared to 1.29 (1.20-1.40; p < 0.001) for AD and 0.66 (0.59-0.73; p < 0.001) for asthma. For CRSwNP treatment, the DA-OSR ROR was 0.97 (0.90-1.03; p = 0.3) for men and 0.78 (0.73-0.83, p < 0.001) for older adults (age > 50). ROR in the DPA for DA-OSR was 12.5 (12.2-12.8; p < 0.001) for any indication and 0.58 (0.53-0.64; p < 0.001) for CRSwNP treatment only. While there are limitations to FAERS, this study confirms the association between dupilumab and OSR for AD treatment, and does not support an association between dupilumab and OSR for CRSwNP treatment. Younger adults experience more DA-OSR in CRSwNP treatment without a specific predilection for sex. IV Laryngoscope, 134:2602-2608, 2024.

The use of benzalkonium chloride in topical glaucoma treatment: An investigation of the efficacy and safety of benzalkonium chloride-preserved intraocular pressure-lowering eye drops and their effect on conjunctival goblet cells.

Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence-based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first-choice treatment option, the most common approach for managing glaucoma is IOP-lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta-analyses investigate potential differences in efficacy and safety between BAK-preserved and BAK-free anti-glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK-preserved eye drops. However, the meta-analyses addressing hyperemia, number of ocular adverse events, and tear break-up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta-analysis finds that there are no differences in the IOP-lowering effect between BAK-preserved and BAK-free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK-preserved and BAK-free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP-lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK-preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative-free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK-preserved travoprost is found to be cytotoxic in a time-dependent manner, while Polyquad®-preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK-preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad-preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)-6 and IL-8, unlike BAK-preserved latanoprost. A review highlights the active and inactive components of IOP-lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro-inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.

Impact of Long-Term Treatment with Belantamab Mafodotin on Safety and Efficacy Outcomes in Patients with Relapsed/Refractory Multiple Myeloma in DREAMM-3

Introduction: DREAMM-3 (NCT04162210) is a randomized study comparing single-agent belantamab mafodotin, a first-in-class antibody-drug conjugate targeting B-cell maturation antigen, to a standard-of-care regimen, pomalidomide plus dexamethasone (Pd). This post-hoc analysis from the DREAMM-3 trial evaluated the safety and efficacy of long-term treatment (≥52 weeks) with belantamab mafodotin compared with Pd, as well as the effects of dose modifications, in adult patients with relapsed/refractory multiple myeloma (RRMM) at third line of therapy or later. Methods: Patients were randomized (2:1) to belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks (Q3W; 21-day cycle) or pomalidomide 4 mg orally once daily (Days 1-21) and dexamethasone 40 mg (20 mg if &amp;gt;75 years) orally once weekly (28-day cycle). Belantamab mafodotin dose reductions or delays were permitted to manage treatment-related Grade 3-4 adverse events (AEs), or Grade 2 AEs that were worsening or had symptoms lasting &amp;gt;7 days. Following AE resolution to Grade ≤1, belantamab mafodotin treatment could resume with or without dose reduction (to 1.9 mg/kg). If no dose delays occurred, patients could receive a maximum of 17 cycles in 52 weeks, hence 17 cycles was used as a threshold to assess long term safety. Ocular exams were performed prior to dosing belantamab mafodotin Q3W up to Cycle 6, then every 3 months if no significant ocular events were reported. Treatment-related ocular AEs were graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 and per the Keratopathy Visual Acuity (KVA) scale. The KVA scale incorporates corneal examination findings and changes in Snellen-equivalent best corrected visual acuity (BCVA) into a composite grade. Ocular AEs are reported as worst-case post-baseline. Efficacy responses (per 2016 International Myeloma Working Group criteria) were assessed Q3W, regardless of treatment delays. Results: As of September 12, 2022, 50/218 (23%) patients were treated with belantamab mafodotin for ≥52 weeks. AEs were reported in all patients treated with belantamab mafodotin for ≥52 weeks. Grade ≥3 AEs occurred in 82% (n=41); the most frequent were reduced visual acuity (24%), thrombocytopenia (18%), and neutropenia (16%). The majority of AEs reported occurred at or before cycle 17. For the most common (&amp;gt;40%) AEs (any grade), few additional events occurred after cycle 17 (1 new occurrence each of dry eye, reduced visual acuity, eye irritation, and thrombocytopenia after cycle 17). Few infections (any grade) occurred after cycle 17 (COVID-19, n=5; viral infection, n=1; pneumonia influenzal, n=1). No patients permanently discontinued treatment due to AEs considered related to belantamab mafodotin. Ocular AEs were reported in 94% (n=47) of patients treated with belantamab mafodotin for ≥52 weeks. The majority of ocular AEs (n=487) were of Grade 1 or 2 severity (88%) and no ocular AEs led to study treatment discontinuation. At the time of data cutoff, 95% (n=41) of patients experiencing Grade ≥2 KVA events had recovered prior to the end of study treatment exposure (defined as last dose + 20 days). Most patients had a dose modification, and no loss of efficacy was observed. The clinical benefit rate (≥minimal response) in these patients was 90% (45/50) and the median time to best response was 6.3 months (range 0.8-18.8). Median duration of response was not reached (NR; 95% CI 17.9, NR) in the subset of patients treated for ≥52 weeks. At the time of data cutoff, 94% (n=47) patients were alive. Conclusions: In patients who received long-term treatment (≥52 weeks), the safety profile of belantamab mafodotin was consistent with previous reports. Despite the need for belantamab mafodotin dose delays and reductions, no patients discontinued study treatment due to belantamab mafodotin-related AEs. During dose delays, clinical responses were maintained or deepened in most cases, demonstrating that management of AEs using dose modifications did not impact clinical activity. Together, this suggests that dose modifications are highly effective in the management of emerging AEs while allowing for sustained clinical benefit. Funding: GSK (207495). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

An Updated Analysis of Ocular Adverse Events and Vision-Related Functioning in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916) is a B-cell maturation antigen-binding antibody-drug conjugate approved as a monotherapy in pretreated patients (pts) with relapsed/refractory multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. In this descriptive analysis, we evaluate the OAEs and their impact on daily functioning in transplant ineligible (TI) pts with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. The study is comprised of 2 Parts: Part 1 evaluates the safety/clinical activity of three different belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd and establishes the recommended phase 2 dose (RP2D). Part 2 further investigates the safety/efficacy of RP2D in two Groups and evaluates two different sets of guidelines for the management of OAEs. In Part 1, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular assessments include best corrected visual acuity (BCVA), using Snellen chart and manifest refraction, and corneal exam using slit lamp microscopy. Ocular symptoms are classified by Common Terminology Criteria for Adverse Events v5.0, while dry eye disease severity and vision-related functioning is assessed with the patient-reported questionnaire Ocular Surface Disease Index (OSDI). In Part 1 of the study, severity of corneal events is assessed with the Keratopathy Visual Acuity scale. This descriptive analysis presents the OAEs in all Part 1 pts over an extensive follow-up period (data cut-off: 05 June 2023). Results Thirty-six pts were included in this analysis, who were followed up for a median of 20.3 months (range 3.2-26.8). At baseline, all pts had ocular comorbidities. Among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4 mg/kg, a meaningful BCVA decline (BCVA &amp;lt;20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%) of the assessments, while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. The most frequently reported ≥Gr 3 ocular symptom was decreased vision, observed in 11 (5%)/ 8 (3%)/ 7 (3%) of the assessments, while ≥Gr3 keratopathy was noted in &amp;lt; 2% of assessments across all cohorts. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the Activities of Daily Living category (ADL) were 6 (3%)/4 (2%)/3 (2%). In terms of missed doses due to OAEs, among 129/138/119 planned belamaf infusions, the number of skipped doses were 53 (41%)/48 (35%)/32 (27%). The overall response rate was 100%, no disease progression was observed over a median follow-up of 20.3 months, and 30 (83%) patients achieved at least VGPR while 19 (53%) achieved at least CR, with a median time to first response of 1 month. Conclusions Over a prolonged follow-up period, the belamaf-Rd triplet, with the extended dosing schedule for belamaf, had a minimal impact in vision-related functioning, as the ‘all/most’ of the time worst answers in the ADL category of OSDI was ≤3% across all cohorts. Furthermore, the frequency of clinically relevant impairment in vision was low, as a meaningful BCVA decline was observed in &amp;lt;10% of assessments, with a rapid time to resolution. Finally, the treatment combination induced rapid, deep and durable responses across all dose levels, with no PD observed. In conclusion, this novel extended belamaf schedule nearly eradicates the risk for clinically relevant ocular toxicity and impact on ADL, without any compromise in clinical activity, suggesting it may be a valid option in the upfront treatment of this frail, elderly and difficult-to-treat pt population.

Prevention of Ocular Toxicity Using Protective Contact Lenses in Multiple Myeloma Patients Receiving Belantamab Mafodotin, Pomalidomide and Dexamethasone: A Sub-Study of the Cmrg-007 Trial

Background: Belantamab mafodotin (belamaf) is a monomethyl auristatin-F containing antibody drug conjugate that targets BMCA on myeloma cells. Single agent belamaf has shown clinical meaningful activity in relapsed/refractory multiple myeloma (RRMM) but ocular adverse events (AEs) affect 53-72% of trials'participants. In DREAMM-2, prophylactic corticosteroid eye drops did not effectively reduce the risk of keratopathy. It is therefore imperative that strategies to mitigate corneal AEs be explored. This 2-part study is designed to evaluate belamaf and pomalidomide/dexamethasone (Pd) in RRMM. Here we report the efficacy and ocular AEs of patients (pts) receiving 2.5 mg/kg (maximum tolerated dose) or 1.92 mg/kg IV belamaf and administrated on various schedules aimed to define the optimal balance of efficacy and tolerability. We also present results of an ocular sub-study exploring the use of bandage contact lens (BCLs) to reduce the risk and severity of belamaf-associated ocular AEs. Methods: Eligibility: &amp;gt; 1 prior lines of therapy (LoT), lenalidomide, proteasome inhibitors exposed, and refractory to the last LoT. Pd was administered per standard of care and belamaf (1.92 or 2.5 mg/kg) Q4W or 2.5 mg/kg Q8W, Q12W or SPLIT equally on days 1 and 8, Q4W. Pts enrolled on the ocular sub-study received the recommended part two dose (RP2D): 2.5 mg /kg Q8W. A BCL (Bausch and Lomb Pure Vision) was placed in the right (R) eye for the 1st 2 doses of belamaf with the left (L) eye serving as control. Subsequently, BCLs were placed in both eyes. Pts wore BCLs for up to 28 days after each belamaf dose. Evaluation by an eyecare specialist for a comprehensive eye exam and BCL placement occurred every 15-28 days during BCLs use and prior to each belamaf dose. Corneal findings were graded (Gr) by the keratopathy and visual acuity (KVA) scale and findings of local infection were reported. Keratitis prophylaxis during BCLs use included gatifloxacin 0.3% or tobramycin 1.3% eye drops. Results: This analysis comprises 92 pts including 14 on the ocular sub-study. Baseline best corrected visual acuity (BCVA) and ocular comorbidities were similar across all cohorts: with median 20/20 BCVA 46.7% R and 50% L eye. Abnormal fundoscopy was 21.7% in R and 16.3% in L eye. There was a trend to lower incidence and less severity of ocular AEs for the 1.92 mg/kg dose (Table 1). Gr 3-4 keratopathy, decrease in BCVA and subjective Gr &amp;gt;2 blurred vision by CTCAE were 33.3% (4/12), 41.7% (5/12) and 25% (3/12) for the 1.92 mg/kg and 75% (9/12), 75% (9/12) and 33.3% (4/12) for 2.5 mg/kg Q4W cohorts. Preliminary data indicated superior clinical efficacy (ORR, &amp;gt;VGPR rate and mPFS) for the 2.5 mg/kg dose, 100% (12/12), 91.7% (11/12) and 25.1 months (11.8-NYR) versus 66.7% (8/12), 63.6% (7/12) and 16.9 months (5.3-19.7) for the 1.92 mg/kg dose (Table 2). To preserve efficacy but reduce ocular AEs additional cohorts exploring 2.5 mg/kg dosed every 8 and 12 weeks were included. Extended dosing schedules showed lower rates of Gr 3-4 keratopathy, decrease in BCVA, and Gr ≥2 blurred vision: 58.3% (7/12), 91.7% (11/12) and 16.7% (2/12) of pts treated Q8W; and 58.3%, 58.3% and 16.7% (2/12) of pts treated Q12W versus the Q4W schedule. Importantly, the efficacy was preserved with ORRs of 91.7% (11/12) and 100% (11/11), &amp;gt;VGPR rates of 83.3% (10/12) and 63.6% (7/11) and mPFS of 18.3 months (95% CI: 10.1-NYR) and 22.5 (95% CI: 8.9-NYR) for Q8W and Q12W groups, respectively. In the ocular sub-study, assessment of R and L eye during the first 2 belamaf doses showed a significant delay in onset of BCVA decrease in the R eye (p&amp;lt;0.0001) compared to the L. Comparing pts treated at the RP2D, moderate to severe (Gr ≥2) keratopathy and decrease BCVA were significantly lower (p=0.0004 and 0.010), in the BCL cohort versus no-BCL group. Further there was a trend towards less symptomatic blurred vision (p=0.256). BCL pts were able to complete 90% of the pre-planned belamaf cycles compared to 70% in the RP2D no-BCL group (p=0.029). No cases of infectious keratitis were reported in the BCL cohort. Conclusions: Our data suggest that extended dosing intervals may be a significant step forward in mitigating corneal AEs of belamaf. This preliminary report on the efficacy of BCLs in 14 pts demonstrates a decrease in moderate to severe corneal AEs and reduction in dose holds for corneal AEs, noting however a short follow up at this time. The data support the further evaluation of BCLs in preventing belamaf associated ocular toxicities.

Evaluation of a Novel Method for the Assessment of Ocular Adverse Events and Associated Functional Impact in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting B-cell maturation antigen, has shown promising efficacy and a favorable tolerability profile in the treatment of multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. Keratopathy and Visual Acuity (KVA) scale was used in most belamaf trials, including the pivotal DREAMM-2, to guide belamaf dose modifications. KVA grading is dependent on an ophthalmologist consultation prior to belamaf administration. Herein, we evaluate a novel approach to guide belamaf dosing in transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Part 1 evaluated the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and established that the recommended phase 2 dose (RP2D) is 1.9 mg/kg, initially administered q8w and, depending on toxicity, adjusted to q12w. Part 2 investigates the safety/efficacy of RP2D in Groups A and B, comprised of 15 pts each, and evaluates two different sets of guidelines for the management of OAEs. In Group A, belamaf dosing is guided by the KVA scale; in Group B, dose modifications are determined by the pts' responses on ocular symptoms and their impact on activities of daily living (ADL), captured by the Vision Related Anamnestic (VRA) tool, and by the presence of ≥Grade (Gr) 3 KVA events (BCVA reduced/corneal findings). VRA is a novel, 9-item physician administered questionnaire designed to assess the frequency of ocular symptoms and their impact on vision-related activities. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation, while ocular symptoms are classified by CTCAE v5.0. Herein, we present the OAEs and the clinical activity of the treatment combination for both Groups of Part 2 (cut-off date 05/06/2023). Results By the cut-off date, twenty-four pts [median age: 75.5 years; male: 16 (66.7%)] had received ≥ 1 belamaf dose in Part 2 and were still on treatment. At baseline, most pts had ocular comorbidities. The median belamaf administrations and number of cycles reached were 3.0/2.0 and 6.5/5.5, for Groups A and B, respectively. A meaningful BCVA decline (BCVA &amp;lt;20/50) with at least 3 lines drop in the better seeing eye, was noted in 5/52 (9.6%) and 5/45 (11.1%) assessments, while BCVA ≤20/200 with at least 3 lines drop was noted in 1/59 (1.7%) and 2/51 (3.9%), respectively. Overall, no ≥Gr 3 ocular symptoms were observed, while the most frequent ≥Gr 2 ocular symptom was dry eye (57/110, 51.8%); also, no ≥Gr3 keratopathies were recorded. Among 66/59 VRA assessments, ocular symptoms and ADL impairment, manifesting for &amp;gt;50% of the time (substantial time) in the last 24 hours prior to belamaf administration, were noted in 2 (3.0%)/9 (15.3%) and 2 (3.0%)/7 (11.9%), respectively. Importantly, numerically similar proportions of KVA events and skipped belamaf doses were noted in both Groups (Table 1). Furthermore, although the sample size of the present analysis does not allow conclusions for the VRA test characteristics, it is notable that in all assessments where eyesight difficulties were reported for substantial time, ≥Gr2 KVA events were also recorded, suggesting a potential association between VRA responses and KVA events, that warrants further investigation. Finally, in terms of clinical activity, for the 19 response-evaluable pts (≥2 efficacy assessments), at a median follow-up of 7.4 months the ORR was 90%/100% in Groups A and B (PR/VGPR: 30%/60%; 66.7%/33.3%) with no disease progression observed. Conclusions In this preliminary descriptive analysis, the VRA tool was safe and effective in informing belamaf dose adjustments in the extended dosing schedule. Recruitment in Part 2 is ongoing and, as data accumulates, future analyses will provide further insight on the potential association of the VRA tool with KVA events, which may eliminate the need for an ophthalmic exam prior to belamaf dosing.

Efficacy and Safety of Processed Amniotic Fluid (pAF) Drops for the Treatment of Ocular Chronic Graft-Versus-Host Disease

Background: Ocular graft-versus-host disease (GVHD) affects more than 50% of patients with chronic GVHD and can lead to debilitating dry or painful eyes, impaired activities of daily living and poor quality of life. Management is mainly supportive, through control of surface inflammation, lubrication, and control of drainage and evaporation. Amniotic fluid (AF) is a rich source of nutrients, cytokines, and growth factors that has antimicrobial and immunomodulatory activities and may have reparative and regenerative roles in human disease. Investigators at the University of Utah developed protocols to collect AF from full-term pregnant women, process and sterile filter AF to separate cytokines and growth factors from residual cells and debris contained in the no-cellular fraction of AF, and treat patients with different conditions. We report the treatment effects and safety of processed AF (pAF) for the treatment of ocular GVHD. Methods: In this randomized, double-blinded, placebo-controlled phase II trial (NCT# 03298815), patients age ≥ 18 years diagnosed within 5 years after allogeneic hematopoietic transplant with ocular GVHD causing dry eye symptoms requiring lubricant drops &amp;gt;3x/day, punctal plugs, thermally cauterized puncta or special eyewear to relieve pain; or inability to work because of ocular symptoms; or loss of vision due to keratoconjunctivitis sicca were enrolled. Patients with any other chronic GVHD treated with &amp;gt;3 lines of therapy beyond corticosteroids with or without calcineurin inhibitors or sirolimus; or had a difference in dryness between both eyes of &amp;gt;2 points by the International Dry Eye WorkShop (DEWS) 2007 report; or were not willing to discontinue the use of medicated lubricant eye drops prior to randomization were excluded. Randomization was performed within participants, with one eye receiving one drop of pAF and the other eye saline treatment (placebo) twice daily for 30 days. In patients wearing scleral lenses, the eye drops were applied prior to lens insertion in the morning and after removal at night. Patients were allowed to resume their medicated eye drops after the 30-day treatment period. The primary objectives were to determine the day 30 overall response (complete and partial response) and safety of pAF. Response type to treatment is defined in Table 1. Key secondary objectives included longitudinal changes in visual acuity and the corneal surface, and patient-reported outcomes. Results: All fifteen patients' eyes were randomized to either pAF or saline treatment. The median age was 61 years (range, 35-72). At enrollment, six patients wore scleral lenses. The median baseline FACT-G score was 88 (range, 58-104). Baseline eye characteristics by treatment are shown in Table 2. Baseline NIH CC eye scores were similar between pAF and saline-treated eyes. The saline-treated group had more eyes with DEWS score 3 (n=7) compared to the pAF group (n=2). All 15 patients completed treatment. The overall response at day 30 in the pAF and saline-treated groups was 25% and 50%, respectively, p=0.38. All responding eyes had a partial response. No treatment-related serious ocular adverse events were observed. Two minor events occurred in the pAF treated eye group, including a change in eyelid position (n=1) and stinging after study drop application (n=1). There was no significant change in visual acuity and corneal surface staining between treatment groups at 30, 60, and 100 days. There was no significant change in the FACT-G score at 30, 60, and 100 days, and there was no significant difference in patient reported eye pain between pAF vs. saline-treated eyes over time (p=0.21). Conclusion: In this study, the primary endpoint of safety was met as there were few adverse events. One quarter of pAF-treated eyes responded. These findings justify evaluating pAF for ocular GVHD in a larger study. Limitations of this study included restricting patients to pAF application to twice a day and the study design of randomizing eyes within each subject as several patients had mild asymmetric disease between the two eyes. Other challenges included having delayed ocular assessments and/or altered perceptions of quality of life due to the COVID19 pandemic.

High Responses Rates with Single Agent Belantamab Mafodotin in Relapsed Systemic AL Amyloidosis

Introduction: Systemic AL amyloidosis, a rare incurable plasma cell disorder, has no approved treatments at relapse. Belantamab mafodotin is an antibody-drug conjugate which targets BCMA antigen approved for relapsed refractory myeloma. We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those traditionally excluded from clinical trials (eGFR&amp;lt;30 ml/min/1.73m 2 and cardiac Mayo stage IIIb disease). Methods: All patients treated with belantamab mafodotin monotherapy at standard dose (2.5 mg/kg) or dose reduction between April 2021 - July 2023. Standardised assessments including measurement of cardiac biomarkers, clonal parameters and imaging were performed and disease assessment was reported as per International Society of Amyloidosis consensus criteria. Results: Twenty-seven patients were included. The median age at was 65 years (range 41-76) and eight (30%) patients were aged &amp;gt;70 years. Eighteen (67%) had λ AL-type and nine (33%) κ AL-type. A median of two organs were involved at baseline (range 1-4) with renal and cardiac involvement in 20 (74%) and 15 (56%) respectively (3 each for Mayo stage IIIa and stage IIIb). The median time from AL amyloidosis diagnosis to first administration of belantamab mafodotin was 69 (range 5-174) months (~6 years) with a median of 3 prior lines of treatment (range 2-6). Prior drug class exposure included proteasome inhibitors (100%), immunomodulatory drugs (81%) and anti-CD38 antibody (81%) therapy. Ten patients (37%) had undergone prior melphalan-conditioned autologous stem cell transplantation. At the time of first belantamab mafodotin dose, the median involved free light chain concentration was 118mg/l (range 31-1778), eGFR was 40 ml/min (range 7 - 120) and a third (9/27) with an eGFR &amp;lt;30 ml/min/1.73m 2. NT-proBNP was 845 ng/l (range 99-70,000). At data cut-off, a median of 5 (range 1-11) doses of belantamab mafodotin were delivered. Of those with evaluable disease, best haematological overall response rate (partial response or better) was 80% (20/25) at a median time to best haematological response of 2 months (95% CI 1-4, range 1-17). Complete response (CR) or very good partial response (VGPR) was achieved in 64% (16/25). Two patients have only had 1 cycle and too early to perform response assessment. Reasons for treatment discontinuation (n=12) were: inadequate response/progression (n=7), keratopathy (n=1), grade 3 thrombocytopenia (n=1), physician choice (n=3: discontinued due to treatment for unrelated metastatic squamous cell carcinoma but remains in CR; facilitation of renal transplant; prior to BCMA-directed CAR-T in VGPR). At a median follow-up of 13 months follow-up (95% CI 4-18, range 1-27) from belantamab mafodotin initiation, 15 patients (56%) remain on therapy. Two patients died (1 due to progressive disease, 1 unrelated) and seven patients progressed and had subsequent line of therapy at a median time of 6 months (95% CI 2-4) in those that had a next line of therapy. Median treatment-free survival or death was 27 months (10-NR), and 1-year treatment-free survival/death was 69% (95% CI 41-86). Median overall survival (OS) is not reached. 1-year OS is 88% (95% CI 59-97). Bilateral microcystic corneal keratopathy, the most frequent adverse event, was seen in 19 (70%) patients (5%; 1/19 grade 4).Ocular adverse events improved in all patients after treatment delay. Only one patient required treatment cessation due to ocular toxicity (despite achieving PR after one dose). Thrombocytopenia was reported in 3 (11%) (grade 3: 1; grade 2: 1). Only two patients remained on the standard dose of 2.5mg/kg for &amp;gt;3 cycles. Nine patients had eGFR &amp;lt;30ml/min and 6/9 started at a dose of 1.25mg/kg with no unexpected side effects (1 patient had grade 3 keratopathy). One patient post-renal transplantation (on tacrolimus and mycophenolate) had no significant toxicity and achieved a CR after cycle 3. No treatment-related deaths, cardiac or renal toxicities observed in our cohort. Conclusion: Belantamab mafadotin has high efficacy and good tolerability in multiply relapsed AL amyloidosis including efficacy in patients otherwise excluded from clinical trials. Treatment-emergent adverse events (especially keratopathy) do not preclude delivery of drug with appropriate dose reductions.

Safety and efficacy of intravitreal injection of conbercept for the treatment of patients with choroidal neovascularization secondary to pathological myopia: Results from the SHINY study.

To evaluate the safety and efficacy of intravitreal injections of 0.5 mg conbercept in patients with choroidal neovascularization secondary to pathological myopia (pmCNV). The 177 pmCNV patients were randomly assigned in a 3:1 ratio to receive conbercept or sham injection, respectively. The conbercept group receive conbercept intravitreal injections administered on a pro re nata (PRN) basis after 3 monthly loading doses. The sham group received three consecutive monthly sham injections and then one conbercept injection followed by PRN conbercept intravitreal injections. At month 3, the mean BCVA for the two groups were improved by 12.0 letters (conbercept group, from 54.05 letters to 66.05 letters) and 0.6 letters (sham group, from 49.77 letters to 50.33 letters), respectively (p < 0.001). The mean central retinal thickness (CRT) at month 3 in the two groups decreased 62.0 μm (conbercept group, from 348.90 μm to 286.18 μm) and 4.4 μm (sham group, from 347.86 μm to 343.47 μm) (p < 0.001). At month 9, the mean BCVA improved by 13.3 letters in the conbercept group and 11.3 letters in the sham group. The mean CRT decreased 73.6 μm in the conbercept group and 55.9 μm in the sham group (p < 0.001). The most common ocular adverse events were associated with intravitreal injections, such as conjunctival haemorrhage and increased intraocular pressure. Intravitreal injections of 0.5 mg conbercept provided improvement in visual and anatomical outcomes in pmCNV patients with low rates of ocular and nonocular safety events.

Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. This systematic review will help to inform and guide future clinical trials.

Double-Masked, Vehicle-Controlled, Randomized, Phase II Study of the Ocular Hypotensive Activity and Safety of VVN539 Ophthalmic Solution

To assess safety and ocular hypotensive efficacy of VVN539 ophthalmic solution in a first-in-human study. Multicenter, double-masked, randomized, vehicle-controlled, dose-response, parallel-comparison study. Sixty-eight subjects with ocular hypertension (OHT) or open-angle glaucoma enrolled at 5 private practices. After washout of ocular hypotensive medications as required, the subjects were randomized to receive either VVN539 ophthalmic solution 0.02%, 0.04%, or vehicle once-daily (QD) in the morning (5 days), once-daily in the evening (6 days) and then twice-daily (6 days). Comparison of VVNM539 to its vehicle in mean intraocular pressure (IOP) at each diurnal time point (8:00am, 10:00am, and 4:00pm) at visit 4 (day 7), visit 5 (day 14), and visit 6 (day 21). Mean IOP decreased throughout dosing in the active groups to between 18 and 20 mmHg in both active groups, to between 22 to 23 mmHg in the vehicle group. VVN539 0.04% was statistically superior to vehicle at all 9 diurnal time points (QD AM, QD PM, and twice daily, P ≤ 0.0109). VVN539 0.02% was statistically superior to vehicle at only 6 of 9 diurnal time points (selected QD times and twice daily). The most common ocular treatment-emergent adverse event was conjunctival hyperemia (11 [47.8%], 10 [4.5%], and 1 [4.3%]), followed by ocular hyperemia (3 [13.0%], 5 [22.7%] and 0), respectively. There were no clinically significant changes of note in visual acuity, biomicroscopy, dilated ophthalmoscopy, blood chemistry, hematology, or cardiovascular measures. In conclusion, the results of this initial phase II study indicate that VVN539 ophthalmic solution showed clinically and statistically significant ocular hypertensive activity and was relatively well tolerated for the treatment of subjects with primary open-angle glaucoma or OHT. Additional studies will be required for a more complete evaluation of the utility of VVN539 ophthalmic solution. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study.

The aim of this study was to assess the long-term safety and efficacy of perfluorohexyloctane (PFHO) ophthalmic drop (formerly NOV03) for treatment of dry eye disease (DED). KALAHARI was a phase 3, multicenter, single-arm, open-label extension study in patients aged 18 years or older with DED associated with Meibomian gland dysfunction who completed the randomized, double-masked, hypotonic saline-controlled GOBI study. Patients instilled 1 drop of PFHO (MIEBO, Bausch + Lomb) 4 times daily in both eyes for 52 weeks. Safety assessments included adverse events, best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, and dilated fundoscopy. Efficacy end points included change from GOBI study baseline in total corneal fluorescein staining and eye dryness score (0-100 visual analog scale). Overall, 208 patients from GOBI (PFHO [n = 97]; saline [n = 111]) were rolled over into KALAHARI. Twenty-nine patients (13.9%) had ≥1 ocular adverse event, with most being mild or moderate in severity; the most common ocular adverse events were vitreous detachment (1.9%), allergic conjunctivitis (1.4%), blurred vision (1.4%), and increased lacrimation (1.4%). Other safety end points were unremarkable. For patients continuing PFHO from GOBI, improvements in total corneal fluorescein staining and visual analog scale dryness scores observed in GOBI were maintained throughout KALAHARI. Patients treated with saline in GOBI and switched to PFHO in KALAHARI showed improvements in total corneal fluorescein staining and visual analog scale scores by week 4 that were maintained for the rest of the study. PFHO was safe and well tolerated and maintained efficacy for improving signs and symptoms of DED in this year-long study of patients with DED associated with Meibomian gland dysfunction.

Risk of ocular adverse events with aromatase inhibitors

ObjectifLes inhibiteurs de l'aromatase (IA) forment une classe de médicaments utilisés dans le traitement adjuvant du cancer du sein. Or, des cas cliniques récents semblent indiquer que les IA pourraient être associés à différents effets indésirables (EI) oculaires. Notre étude se penche sur le risque d'EI oculaires chez les patients qui prennent des IA. MéthodeOn s'est servi de la base de données sur les effets indésirables (Adverse Events Reporting System) de la Food and Drug Administration (FDA) américaine pour les années 2004 à 2022 afin de réaliser une analyse de disproportionnalité. On a extrait tous les cas d'effets secondaires oculaires (traction vitréomaculaire, œdème maculaire, dépôts rétiniens, occlusion de l'artère rétinienne, trou maculaire, hémorragie rétinienne, uvéite, déchirure de la rétine, décollement de rétine, sécheresse oculaire, blépharite et neuropathie optique) en lien avec l'administration des 3 IA (anastrozole, létrozole et exémestane). À titre de groupe témoin, on a procédé à la même recherche sur le trastuzumab. Ont été calculés les rapports de cotes (ROR, pour reported odds ratios) et les intervalles de confiance (IC) à 95 % correspondants. RésultatsNous avons découvert 322 EI oculaires d'intérêt en lien avec l'administration des 3 IA et 55 EI en lien avec l'administration du trastuzumab. L'anastrozole a eu le plus grand nombre d'EI (n = 163); on a enregistré une forte association entre ce médicament et la traction vitréomaculaire (ROR = 665; IC à 95 % : 352–1255), l’œdème maculaire (ROR = 37; IC à 95 % : 25–54), les dépôts rétiniens (ROR = 11; IC à 95 % : 2–77) et l'uvéite (ROR = 6; IC à 95 % : 4–9). On a observé une forte association entre le létrozole et les dépôts rétiniens (ROR = 8; IC à 95 % : 1–57) et l'occlusion des artères rétiniennes (ROR = 6; IC à 95 % : 3–11). Enfin, on a noté une forte association entre l'exémestane et les trous maculaires (ROR = 10; IC à 95 % : 3–30). ConclusionL'analyse de disproportionnalité a mis au jour une hausse du risque d'EI oculaires en lien avec chacun des IA. Compte tenu des résultats de notre étude, il est important que les médecins, surtout les oncologues et les ophtalmologistes, fassent preuve de vigilance chez les patients qui reçoivent des IA pour pouvoir intervenir sans délai afin d’éviter la survenue d'autres affections oculaires.

Long-Term Safety and Efficacy Results of Belantamab Mafodotin Plus Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Part 1 Analysis from the Phase 1/2 Belard Trial

Introduction The preferred upfront treatment of transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of the combination of lenalidomide and dexamethasone (Rd) with a third antimyeloma agent of a different mechanism of action (e.g., proteasome inhibitors or anti-CD38 monoclonal antibodies). Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting BCMA, has shown efficacy in pretreated MM pts, while preclinical data demonstrate synergy between belamaf and lenalidomide, with no overlapping toxicities. Thus, there is a strong rationale for investigating the belamaf-Rd triplet in TI NDMM pts. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Eligible are adult pts with ECOG PS 0-2 and adequate organ function. Part 1 evaluates the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and establishes the recommended phase 2 dose (RP2D). In this part, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation. Ocular symptoms are classified by CTCAE v5.0, while the Ocular Surface Disease Index (OSDI) captures dry eye disease and activities of daily living (ADL).Herein, we present updated safety and efficacy results of all Part 1 pts with an extended follow-up time (cut-off date 05/06/2023). Results Of the 36 pts [median age: 72.5 years; male: 19 (53%)] in Part 1, 29 (81%) are still on treatment, while 7 (19%) have discontinued [6 pts due to belamaf-unrelated fatal events: (COVID-19: 1/1/2; Pneumonia: 1/1/0, for cohorts 2.5/1.9/1.4 respectively); 1 pt withdrew consent]. The median belamaf administrations and number of cycles reached were 6/7/7 and 20.0/22.5/20.0, for the respective cohorts. The most common (≥10% of pts) non-ocular ≥ Gr3 treatment-emergent adverse events were fatigue (21 pts, 58%; [7 (58%)/7 (58%)/7 (58%)]), diarrhoea (8 pts, 22%; 2 (17%)/3 (25%)/3 (25%)]), rash (6 pts, 17%; [2 (17%)/2 (17%)/2 (17%)]), COVID-19 (5 pts, 14%; [2 (17%)/1 (8%)/2 (17%)]) and insomnia (4 pts, 11%; 0/4 (33%)/0]) , while no ≥Gr3 thrombocytopenias and infusion-related reactions were reported. Regarding ≥Gr3 infections other than COVID-19, pneumonia was reported for 3 (8%) pts [1/1/1 (8%)] and lower respiratory tract infection for 1 (3%) pt [0/0/1(8%)]. Regarding ocular adverse events (OAEs), among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4, a meaningful BCVA decline (BCVA &amp;lt;20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%), while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. Across all cohorts, the most frequently reported ≥Gr 3 ocular symptom was decreased vision (26/665, 4%), while ≥Gr3 keratopathy was noted in &amp;lt;2% of assessments. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the ADL category were 6 (3%)/4 (2%)/3 (2%). The overall response rate was 100% across all cohorts: More specifically CR or better was achieved by 7 (58%)/6 (50%)/6 (50%), VGPR by 3 (25%)/5 (42%)/3 (25%) and PR by 2 (17%)/1 (8%)/3 (25%) pts in cohorts 2.5/1.9/1.4, with a median time to first response of 1 month. Finally, at a median follow-up of 20.3 months, no disease progression was observed, median PFS and median time to progression were not reached ( Figure 1) and responses continue to deepen across all cohorts. Conclusions Over an extended follow-up period, the belamaf-Rd triplet has proven a safe and effective combination for the upfront treatment of TI NDMM pts, with no long-term safety signals. Furthermore, the extended dosing schedule for belamaf had a minimal impact in vision-related functioning, as very low rates of meaningful BCVA decline and “most/all” OSDI responses were noted across all cohorts, with a rapid time to resolution. Meanwhile, a very promising clinical activity is observed, with rapid, deep and durable responses across all dose levels. Consequently, after validation with bigger pt numbers, this novel combination may well be a very attractive frontline option for this vulnerable and difficult-to-treat pt population.

Strategic combination of cultivated oral mucosal epithelial transplantation and postoperative limbal-rigid contact lens-wear for end-stage ocular surface disease: a retrospective cohort study

PurposeTo provide the long-term outcome of patients with end-stage severe ocular surface disease (OSD) consecutively treated with cultivated oral mucosal epithelial transplantation (COMET) followed by limbal-rigid contact lens (CL)-wear therapy.DesignRetrospective...

A Phase I/II Single Arm Study of Belantamab Mafodotin, Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Planned Interim Analysis of Safety and Efficacy. Amarc 19-02 Belacard Study

Introduction Belantamab Mafodotin (Belamaf, B), a first in class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate, is efficacious in triple-class exposed, relapsed and refractory multiple myeloma (RRMM). Combination therapy with carfilzomib and dexamethasone (Kd) is potentially synergistic through different anti-myeloma mechanisms of action. We report here a planned interim analysis of safety and responses after the first two cycles of combination therapy. Methods BelaCarD is an ongoing, single-arm, multicentre phase I/II study evaluating 8-weekly B dosing schedule in combination with Kd in patients (pts) with RRMM after 1-3 lines of therapy. B (2.5mg/kg) was administered intravenously (IV) on day (D)1 of every second 28D cycle; K 70mg/m2 IV D1 (20mg/m2 on C1D1), D8 and D15 of every cycle and dexamethasone 40mg weekly (20mg/m2 for pts &amp;gt;75 years). Treatment was continued until disease progression. Corneal adverse events (AEs) were graded as per the keratopathy and visual acuity (KVA) scale and all other AEs as per CTCAEv5. Confidence interval coefficients for response rates (RR) were adjusted using an alpha-spending function. The primary objective is progression free survival (PFS). Results As of 13 th July 2023, 65 pts (67% male) of the intended 70 have been enrolled. 55 pts (62% male) received minimum 2 cycles of B-Kd and were included in the protocol-specified interim analysis. The median age was 69.7 years (48-81); 18 pts (33%) had high-risk cytogenetics either at diagnosis or screening. ISS stage I, II, III occurred in 47.3%, 23.6% and 10% respectively. 25.5%, 38.2% and 34.6% pts had 1, 2 and 3 prior lines of therapy respectively including (exposed/refractory) bortezomib (90.9%/42%), K (3.6%/50%), lenalidomide (52.7%/44.8%), pomalidomide (5.5%/33%), anti-CD38 monoclonal Ab (mAb) (30.9%/52.9%), autologous stem cell transplant (ASCT) (41.8%). The median number of cycles received was 9 (2-27). Treatment-related AEs were reported in 93% of pts (Gr3 60%, Gr4 13%); most frequent were (all grade, Gr3, Gr4): blurred vision (40%, 7.3%, 0%), nausea/vomiting (29.1%, 3.6%, 0%), insomnia (23.6%, 10.9%, 0%), thrombocytopenia (23.6%, 10.9%, 5.5%). Ocular AEs occurred in 42 (79.2%) out of 53 evaluable pts including decline in best corrected visual acuity (BCVA) (total 77.2%, Gr1 9.4%, Gr2 33.9%, Gr3 33.9%) and keratopathy (K) (total 75.4%, Gr1 5.6%, Gr2 22.6%, Gr3 47.2%). Median time to reach worst-grade BCVA and K was 106 (25-309) and 76.5 (25-231) days respectively. Median time to return to Gr ≤1 BCVA and K was 61 (28-322) and 94 (30-326) days respectively. Ten pts had B-related SAEs (Gr 1/2 n=2, Gr 3 n=6, Gr 4 n=1, one pt died of sepsis). A second treatment-related death was due to pneumonia. Six pts discontinued therapy due to treatment-related AE including 4 due to B (corneal toxicity n=2, sepsis n=1, proteinuria n=1). Overall RR and ≥ VGPR by end of cycle 2 were 80% (97%CI: 65.3 - 90.5) and 40% (97%CI: 25.5 - 55.9) respectively. At estimated median potential follow-up of 13 months (4-38), the preliminary estimate of PFS at 24m was 56.1%. Conclusion B-Kd with an extended B schedule demonstrates a manageable safety profile. The preliminary efficacy data is encouraging with deep responses observed after only 2 cycles of therapy. Recruitment is close to completion with the main analysis to be conducted once all pts have completed the 12-month assessment. Acknowledgement: pts, their families and participating AMaRC members and sites as well as the support of GSK and funding support from the Victorian Cancer Agency.

The Efficacy and Safety of Standard versus Soft Topical Steroids after Cataract Surgery: A Systematic Review and Meta-analysis

Review of the efficacy and safety of standard versus soft topical steroid application after cataract surgery. The control of postoperative inflammation is the mainstay of treatment after cataract surgery. However, no consensus exists regarding the postoperative steroid of choice. Basing the choice of topical postoperative steroidal treatment on high-quality data regarding both risks and benefits of various drugs would be advantageous for both patients and clinicians. A systematic search of the PubMed, Scopus, and Embase electronic databases for all peer-reviewed published randomized control trials that included clinical outcomes of topical steroidal treatment after uneventful cataract surgery was performed. Individual study data were extracted and evaluated in a weighted pooled analysis including grading of total anterior chamber (AC) inflammation, AC cells, AC flare, postoperative visual acuity (VA), intraocular pressure (IOP), and rate of adverse events (AEs). Overall, 508 studies were found, of which 7 were eligible for the systematic review and ultimately were included for analysis, reporting on 593 patients from 5 countries. Age of included patients, when available, ranged between 3.7 and 73.4 years. Follow-up data were available for analysis at 1, 7, and 28 days after surgery. Except for a significantly lower grade of AC flare in the standard steroid group at day 7 (standardized mean difference, 0.26; 95% confidence interval, 0.05-0.47; I2= 0%), inflammatory activity measurements displayed insignificant differences at every other follow-up (days 1 and 28 after surgery). Pooled analysis of IOP at each follow-up demonstrated a higher IOP at the 7-day visit in the standard steroid group, whereas IOP at other time points was comparable among the groups. Qualitative analysis of ocular AEs showed similarities among the groups. The findings of this study suggest that for the average patient, both groups produce a comparable effect on both AC inflammation and postoperative IOP and VA. The author(s) have no proprietary or commercial interest in any materials discussed in this article.