Phase 2b/3 results for nAMD candidate KSI-301 revealed by Kodiak Sciences


KSI-301, a treatment for n-AMD patients, failed to 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 results from its Phase 2b/3, randomized, double-blind, active-controlled clinical trial evaluating the efficacy, durability, and safety of KSI-301, a novel antibody- biopolymer, in treatment-naïve subjects with neovascular (wet) age-related macular degeneration (nAMD).

Although the treatment did not show non-inferior visual acuity gains compared to aflibercept, the study results demonstrate that it is safe and well tolerated in patients. No other safety signals were reported.

According to the company, the trial randomly assigned 559 participants, about 80% of whom were enrolled in the United States. The study had two treatment arms: KSI-301 5 mg on a flexible, long-interval regimen and aflibercept 2 mg on a fixed, short-interval regimen.

In a press release, the company noted that in the study, three monthly loading doses were given to all subjects at 0, 4 and 8 weeks. Subjects on aflibercept were then treated at fixed intervals of 2 months. Subjects on KSI-301 were assessed from 3 months after the end of the loading phase (i.e., from 20 weeks) and, based on predefined disease activity criteria , were treated every 3, 4 or 5 months.

Accordingly, patients in the KSI-301 group did not receive dosing more frequently than every 3 months at any time during the study after the loading phase. The primary endpoint of the study was the mean 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 included with a correction such as glasses) from baseline to year 1.

For assessment of the primary efficacy endpoint, KSI-301 patients from the three groups (dosed every 3, 4, or 5 months) were pooled and their BCVA 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 gains in non-inferior visual acuity for subjects receiving prolonged doses compared to aflibercept given every eight weeks.

A year 1 pre-specified secondary analysis assessing durability showed that 59% of patients in the KSI-301 arm achieved a five-month dose with visual acuity gains and anatomical improvements comparable to those in the aflibercept group global.

KSI-301 was safe and well tolerated in the study, with no new safety signals identified.

Victor Perlroth, MD, CEO of Kodiak, noted in a press release that allowing treatment with KSI-301 no more often than every 12 weeks after the loading phase for each patient has proven insufficient.

“Nevertheless, we believe the results demonstrate a clear anti-VEGF effect, strong durability and a reassuring safety profile,” Perlrith said in a statement. “We believe these data continue to support the potential of our ABC platform to significantly extend treatment intervals in retinal disorders in a safe and convenient way.

Perlroth noted that going forward, the company’s BEACON study in retinal vein occlusion will have the primary endpoint visit completed in all patients in June with frontline data expected to follow shortly thereafter.

“For our long-interval GLEAM and GLIMMER studies in diabetic macular edema as well as the short-interval DAYLIGHT study in wet AMD, we expect top-notch data in early 2023,” he added. . “As our understanding of KSI-301 and different patient populations with retinal vascular disease evolved, so did our study designs.”

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 (stricter 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 went too far for approximately 30% of patients who could have benefited from greater than minimum VEGF inhibition every 3 months of the study,” said Carl Regillo, MD, Head of Retina Service at Wills. Eye Hospital of Philadelphia and a study investigator. “Visual acuity in these patients deteriorated and therefore KSI-301-treated patients overall did not achieve non-inferior visual acuity results compared to aflibercept-treated patients. .”

Regillo noted that the clear and unprecedented durability of effect for the majority of KSI-301 patients treated with intravitreal drug should be a significant advancement for the wet AMD patient community.
“KSI-301 at year 1 brought more than half of patients on a 5-month diet to the 20/40 vision required to operate a motor vehicle,” he said. “Kodiak’s ongoing Phase 3 program aims to further clarify the important role that KSI-301 may 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 are already providing more frequent treatment for patients with high needs.

“The DAYLIGHT study with its proactive monthly dosing should answer the question of the efficacy of early and intensive treatment in wet AMD with KSI-301,” Regillo concluded.

Additionally, Jason Ehrlich, MD, PhD, Chief Medical Officer and Chief Development Officer of Kodiak, noted that based on the observations and retreatment criteria used in the company’s earlier Phase 1b study, the criteria for Study dosing interval selection achieved the important goal of identifying patients who might do well with each 5-month dose of KSI-301/

“This group represented the majority of patients receiving KSI-301,” he explained. “At the same time, the data suggests that KSI-301 patients with persistent or early disease activity may have received treatment more frequently than the study parameters allowed.”

Ehrlich pointed out that at the time the company designed the study, it was thought important to expand all patients with wet AMD to every 3 months or more, and the company designed its study in part. with this goal in mind.

“The ongoing DAYLIGHT study should clearly address the question of whether an intensive dose of KSI-301 provides sufficient VEGF inhibition for this large minority of wet AMD patients,” Ehrlich said.

Ehrlich also pointed out in the press release that from a safety perspective, intraocular inflammation occurred in a low single-digit percentage of KSI-301 patients (3.2%), compared to 0.0% of patients. treated with aflibercept.

“Recent wet AMD studies have reported rates of intraocular inflammation 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 has been observed,” he concluded. “We believe that these safety data together with the safety observations in the ongoing Phase 3 studies continue to suggest a safety profile for KSI-301 comparable to aflibercept.”

Full study results are expected to be presented at an upcoming medical symposium.


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