Albert Liao, MD
Stein Eye Institute, UCLA
Los Angeles, CA
The late breaking abstract session 1, moderated by Timothy Murray MD, MBA, FASRS and Christina Weng MD, MBA, FASRS, saw five presenters covering results from a variety of novel therapeutics.
48-Week End of Study Results from BEHOLD Phase 2 Study for UBX1325 in Patients with Diabetic Macular Edema
UBX1325, a novel Bcl-xL inhibitor senolytic agent, improved visual acuity and led to ~50% of patients with diabetic macular edema (DME) achieving a rescue-free interval of at least 48 weeks, Arshad M. Khanani, MD, MA, reported. This successful outcome highlights the potential of Bcl-xL inhibitiors for disease modification.
Patients with DME with repeated prior anti-VEGF treatments (average 4.1 injections in prior 6 months), residual retinal fluid (average 439.6 um), and visual acuity deficit (average 61.4 ETDRS letters), were enrolled in the BEHOLD study, a phase 2 clinical trial designed to investigate the safety and efficacy of UBX1325. Patients were randomized to an injection of UBX1325 (n =32) or sham (n= 33) with the last anti-VEGF treatment being given 3-6 weeks prior to randomization.
48-week results showed UBX1325-treated patients had a marked drop in need for anti-VEGF rescue beyond 18 weeks compared to sham-treated patient through 48 weeks. Rescue criteria was either a decrease of 10 ETDRS or more letters from any peak value or an increase in CST of 75 um or more from baseline. Median time to first rescue in UBX1325-treated patient was > 48 weeks (at least 30 weeks greater than Sham arm). Approximately 50% of UBX-treated patients went without rescue through 48 weeks (versus < approximately 20% of sham patients).
UBX1325-treated patients demonstrated significant improvement in BCVA (6.2 letters better than baseline at 48 weeks excluding post rescue data). There were no instances of intraocular inflammation, endophthalmitis, retina artery occlusion or vasculitis in the treated group. The follow up Phase 2b ASPIRE study will compare UBX1325 with aflibercept in patients with advanced DME.
KSI-301 Anti-VEGF Antibody Biopolymer Conjugate for Diabetic Macular Edema: Primary Endpoint Efficacy and Safety Outcomes of the GLEAM and GLIMMER Phase 3 Pivotal Studies
The KSI-501 agent (tarcocimab tedromer), a novel anti-VEGF antibody biopolymer conjugate, did not meet the primary endpoint in the GLEAM and GLIMMER studies and failed to demonstrate non-inferior visual acuity gains compared to aflibercept, Charles C. Wykoff, MD, PhD, FASRS, reported.
The GLEAM and GLIMMER trial were a pair of identically designed, randomized, double-masked, multi-center Phase 3 non-inferiority studies of tarcocimab tedromer 5 mg versus aflibercept 2mg in treatment-naïve diabetic macular edema (DME). Tarcocimab was individually dosed based on patient-specific disease activity assessments and was dynamically adjusted between q8 and q24 weeks after three initial loading doses. Aflibercept was dosed at q8 weeks interval after three initial loading doses. GLEAM enrolled 230 patients in the tarcocimab arm and 230 patients in the aflibercept arm. GLIMMER enrolled 231 patients in the tarcocimab arm and 228 patients in the aflibercept arm.
Baseline ocular characteristic were well-matched between groups in each study and were typical of treatment-naïve DME patients. While ≥ 50% of tarcocimab patients achieved consistent 6-month dosing and ~75% of tarcocimab patients successfully completed at least one 5-6 month interval, tarcocimab did not demonstrate non-inferiority in mean change in BCVA compared to aflibercept. Mean change in BCVA from baseline at 60 and 64 weeks was 6.4 (standard deviation 8.8) for tarcocimab versus 10.3 (standard deviation 8.1) for aflibercept for GLEAM (non-inferiority p-value = 0.4162). Mean change in BCVA from baseline at 60 and 64 weeks was 7.4 (standard deviation 11.2) for tarcocimab versus 12.2 (standard deviation 10.1) for aflibercept for GLIMMER (non-inferiority p-value = >0.9999).
Rates of common ocular adverse events, including rates of intraocular inflammation, were low in both treatment groups. However, there was an imbalance of cataract observed. In the pooled GLEAM and GLIMMER data, 89 of 458 tarcocimab patients (19.4%) had cataracts in the study eye, compared to 40 of 459 (8.7%) for the aflibercept arm up at 64 weeks. This imbalance was not seen in the DAYLIGHT study, a previous Phase 3 study of tarcocimab in patients with wet age-related macular degeneration.
According to Dr. Wykoff, several insights resulted from this trial. While the matched loading phase was not the problem, tarcocimab did have two fewer initial doses compared to aflibercept due to the study design, which likely had an impact on the BCVA. In addition, the main difference in BCVA was noted in the maintenance phase with the unexpected cataract finding as the main driver. A separate analysis was conducted that showed that pseudophakic patients did well on tarcocimab with similar BCVA to aflibercept. Mechanisms behind cataract development are being explored.
Given these results, further development of tarcocimab is being discontinued by Kodiak Sciences INC.
Efficacy and Safety of CT-P42 compared to Reference Aflibercept in Diabetic Macular Edema: 24-Week Results from the Phase 3 CT-P42 3.1 Study
Biosimilar aflibercept molecule CT-P42 performed just as well as reference aflibercept, according to David M. Brown, MD.
“The regulatory pathway is one clinical trial that is well controlled showing that it has to perform the same as the reference, which is 2 mg of aflibercept,” explained Dr. Brown.
The study design randomized patients with diabetic macular edema (DME) into 2 populations: 4 loading doses of CT-P42 molecule followed by a q8 week dosing (n = 180) versus 4 loading doses of reference aflibercept followed by q8 weeks dosing (n = 180). The primary end point was BCVA at 8 weeks. Secondary endpoint was visual acuity at 52 weeks, both for safety and efficacy.
Baseline disease characteristics were similar between the two groups. Mean BCVA change for CT-P42 at 8 weeks was 9.43 (Standard error 0.798) versus 8.85 (standard error 0.775) for aflibercept. Mean change from baseline in BCVA by visit at 24 weeks was nonsignificant between the two investigational groups and the proportion of patients who gained ≥ 5/10/15 ETDRS letters were similar between the groups across all post-baseline visits. Central subfield thickness was improved in both treatment groups.
Safety profile was similar in both treatment groups, including the rate of intraocular inflammation.
Impact of Faricimab versus Aflibercept on Epiretinal Membrane Formation Over 2 Years in Eyes with Diabetic Macular Edema in the YOSEMITE/RHINE Phase 3 Trials
Faricimab dosed every 8 weeks resulted in a significant reduction in the risk of epiretinal membrane (ERM) formation versus aflibercept dosed every 8 weeks in patients with diabetic macular edema, reports Glenn J. Jaffe, MD
Incidence of ERM after intravitreal injections in eyes with DME over 24 months was 9.5%. Additionally, ERMs removed from eyes with ischemic retinal disease were noted to have elevated Ang-2 levels, explained Dr. Jaffe.
The YOSEMITE/RHINE Phase 3 Trial was the first time ERM development has been presented from a phase 3 trial setting. Post hoc analysis of patients with no ERM at baseline were divided into faricimab dosed every 8 weeks (n = 619), faricimab treat and extend (n = 618), and aflibercept dosed every 8 weeks (n 604).
Through week 100, there was a 52% reduction in the risk of ERM formation in patients dosed with faricimab q8 weeks versus aflibercept q8 weeks. Patients who developed ERMs tended to have worse BCVA, worse central subfoveal thickness, and greater presence of intraretinal fluid and subretinal fluid at 2 years compared to patient who did not develop ERMs.
In the faricimab treat and extend population, only 25% (7/28) of patients who developed an ERM could be extended out to q16 weeks versus 64.3% (332/516) of patients who did not develop an ERM. These results suggest a potential anti-fibrotic effect for faricimab.
Phase 3 Randomized Studies of Ciliary Neurotrophic Factor-Producing Revakinagene Taroretcel (NT-501) to Treat Macular Telangiectasia Type 2
Revakinagene taroretcel (NT-501) is a first-in-class encapsulated cell therapy which leads to a decrease in retinal degeneration in patients with macular telangiectasia Type 2, states Emily Chew, MD.
NT-501 consists of a membrane complex encapsulating RPE cells which are genetically engineered to produce neurotrophic factors. This is surgically implanted into the vitreous and stably anchored to the sclera. Previous phase 2 trials had demonstrated greater preservation of retinal sensitivity and reading speed in patients receiving NT-501.
NTMT-03-A and NTMT-03-B were identically designed phase 3 randomized (1:1) sham-controlled studies of NT-501. Patients received NT-501 or sham procedure in 1 study eye. NTMT-03-A enrolled 58 patients who received NT-501 and 57 patients who received sham. NTMT-03-B enrolled 59 patients who received NT-501 and 54 patients who received sham. Primary endpoint was the rate of ellipsoid zone (EZ) loss from baseline through 24 months.
Secondary efficacy data examined aggregate sensitivity of microperimetry within the areas of EZ loss and monocular reading speed at 24 months. Secondary safety profiles included proportion of patients with a ≥ 15 ETDRS letter loss in BCVA at any visit and the proportion of patients with treatment-emergent serious adverse events.
Key baseline demographic and clinical characteristics were all similar. Participants were primarily white and female, had a mean age of ~60 years, and had a baseline visual acuity of ~ 20/40.
In NTMT-03-A, treatment with NT-501 led to a decreased mean change from baseline EZ area loss over time as well as decreased absolute size of EZ area loss over time. This led to a 56.4% reduction in retinal degeneration. Similar results were seen in NTMT-03-B, leading to a 29.2% reduction in retinal degeneration.
For secondary endpoints, retinal sensitivity was better preserved in NTMT-03-A, but there was no significant difference in NTMT-03-B. Reading speed was preserved in patients treated with NT-501 but not with sham.
Treatment-related serious ocular adverse events were uncommon and predominantly related to complications during surgery. These results demonstrate that intraocular delivery of CNTF using NT-501 is safe and effect for treatment of MacTel Type 2.
