KSI-301, a therapy for patients with nAMD, did not meet the primary endpoint of showing non-inferior visual acuity gains compared to aflibercept given every eight weeks; however, it was safe and well-tolerated with no new or unexpected safety signals.
Kodiak Sciences Inc. announced top-line results from its randomized, double-masked, active comparator-controlled Phase 2b/3 clinical trial evaluating the efficacy, durability and safety of KSI-301, a novel antibody biopolymer conjugate, in treatment-naïve subjects with neovascular (wet) age-related macular degeneration (nAMD).
While the therapy failed to show non-inferior visual acuity gains compared the aflibercept, the study results demonstrate that it is safe and well-tolerated in patients. No additional safety signals were reported.
According to the company, the trial randomly assigned 559 participants, approximately 80% of whom were enrolled in the United States. The study had two treatment arms: KSI-301 5mg on a flexible long-interval regimen and aflibercept 2mg on a fixed short-interval regimen.
In a news release, the company noted that in the study, three monthly loading doses were administered to all subjects at 0-, 4- and 8-weeks. Subjects on aflibercept were then treated at fixed 2-month intervals. Subjects on KSI-301 were assessed starting 3 months after the completion of the loading phase (i.e. beginning at 20 weeks) and, based on predefined disease activity criteria, were treated every 3-, 4-, or 5-months.
As a result, patients in the KSI-301 group did not receive dosing more frequently than every 3 months at any point in the study after the loading phase. The primary endpoint of the study was the average change in best-corrected visual acuity (BCVA) score (a measure of the best vision a person can achieve when reading letters on an eye chart, including with correction such as glasses) from baseline at year 1.
For the assessment of the primary efficacy endpoint, KSI-301 patients in all three groups (dosed every 3, 4 or 5 months) were pooled together and their BCVA was compared as a group to the aflibercept group (dosed every 2 months).
The results show that, although KSI-301 demonstrated strong durability and was safe and well tolerated, it did not meet the primary efficacy endpoint of showing non-inferior visual acuity gains for subjects dosed on extended regimens compared to aflibercept given every eight weeks.
A pre-specified secondary analysis at year 1 assessing durability showed 59% of patients in the KSI-301 arm achieved five-month dosing with visual acuity gains and anatomic improvements comparable to the overall aflibercept group.
KSI-301 was safe and well tolerated in the study, with no new safety signals identified.
Victor Perlroth, MD, Kodiak's CEO, noted in a news release that allowing treatment with KSI-301 no more often than every 12 weeks after the loading phase for every patient turned out to be insufficient.
"Nonetheless, we believe the results demonstrate a clear anti-VEGF effect, strong durability and a reassuring safety profile,” Perlrith said in a statement. “We think that these data continue to support the potential of our ABC Platform to significantly extend treatment intervals in retinal disorders in a safe and convenient manner.”
Perlroth noted that looking forward, the company’s BEACON study in retinal vein occlusion will have the primary endpoint visit completed in all patients in June with top-line data anticipated to follow shortly thereafter.
“For our GLEAM and GLIMMER long-interval studies in diabetic macular edema as well as the DAYLIGHT short-interval study in wet AMD, we expect top-line data in early 2023,” he added. “As our understanding of KSI-301 and the different patient populations within retinal vascular diseases evolved, our study designs have also evolved.”
According to Perlroth, a key factor that likely contributed to this Phase 2b/3 study missing its primary endpoint – undertreatment of a minority of patients – is addressed in BEACON (proactive dosing every 8 weeks) and GLEAM and GLIMMER (tighter dynamic retreatment criteria and dosing as frequently as every 8-weeks) and is not present in DAYLIGHT in which all patients are proactively treated on an every 4-week regimen.
"We learned that the study design stretched it too far for the roughly 30% of patients who could have benefited from more VEGF inhibition than the minimal every 3 months in the study," said Carl Regillo, MD, chief of the Retina Service at Wills Eye Hospital in Philadelphia and a study investigator. "These patients' visual acuity deteriorated, and consequently the KSI-301 treated patients overall did not achieve non-inferior visual acuity outcomes compared to the aflibercept treated patients."
Regillo noted that the clear and unprecedented durability of effect for the majority of KSI-301 patients treated with an intravitreal medicine is expected to be a significant advance for the wet AMD patient community.
“KSI-301 at year 1 brought more than half the patients on an every 5-month regimen to the 20/40 vision required to drive a motor vehicle,” he said. “Kodiak's ongoing Phase 3 program is intended to further clarify the important role KSI-301 can play in the treatment of retinal vascular disorders.”
Regillo also noted in the release that retinal vein occlusion and diabetic macular edema are very different diseases from wet AMD, and Kodiak's BEACON, GLEAM and GLIMMER study designs importantly already provide more frequent treatment for high-need patients.
“The DAYLIGHT study with its proactive monthly dosing is expected to answer the question as to the effectiveness of early and intensive treatment in wet AMD with KSI-301,” Regillo concluded.
Moreover, Jason Ehrlich, MD, PhD, chief medical officer and chief development officer of Kodiak, pointed out that building on the observations and retreatment criteria used in the company’s earlier Phase 1b study, the study's dosing interval selection criteria achieved the important goal of identifying patients who could do well with every 5-month dosing of KSI-301/
“This group represented a majority of patients receiving KSI-301,” he explained. “At the same time, it appears from the data that the KSI-301 patients with persistent or early recurrent disease activity may have benefited from treatment more frequently than what the study parameters allowed.”
Ehrlich pointed out that at the time the company designed the study, it was thought that extending all wet AMD patients to every 3-month or longer dosing was important, and the company designed its study in part with this goal in mind.
“The ongoing DAYLIGHT study should clearly address the question of whether intensive dosing with KSI-301 provides sufficient VEGF inhibition for this important minority of patients living with wet AMD,” Ehrlich said.
Ehrlich also pointed out in the news release that on the safety front, intraocular inflammation occurred in a low single-digit percent of KSI-301 patients (3.2%), as compared to 0.0% of patients treated with aflibercept.
“Recent wet AMD studies have reported intraocular inflammation rates with aflibercept of 1–4.5%. In all cases reported in our study, the clinical finding of inflammation resolved, and no cases of intraocular inflammation with vascular occlusions were observed,” he concluded. “We believe that these safety data coupled with the safety observations across the ongoing Phase 3 studies continue to suggest a safety profile for KSI-301 comparable to aflibercept.”
Full results from the study are expected to be presented at a future medical symposium.