Kodiak Sciences Starts Phase 3 ALTO Trial of KSI-501 in Diabetic Macular Edema

Global Study Begins to Test a Dual-Target Retinal Therapy

Kodiak Sciences Inc. has started enrolling patients in the global Phase 3 ALTO trial evaluating KSI-501 in people with diabetic macular edema (DME).

KSI-501 is an investigational bispecific therapy designed to target two pathways involved in retinal disease: interleukin-6 (IL-6)-driven inflammation and vascular endothelial growth factor (VEGF)-driven vascular leakage and abnormal blood vessel growth.

The company is developing KSI-501 as a potential new treatment for patients who continue to experience retinal swelling and vision problems despite existing anti-VEGF treatments.

The ALTO study is the second registrational Phase 3 trial of KSI-501. The first is the DAYBREAK study, which is evaluating the therapy in patients with wet age-related macular degeneration (wet AMD).

Why Kodiak Is Targeting Both IL-6 and VEGF

VEGF has been a major target in the treatment of diabetic macular edema for years.

Anti-VEGF medicines can reduce fluid buildup in the retina and improve vision for many patients. However, some patients continue to have retinal fluid even after repeated treatment. Many also need frequent eye injections to maintain their results.

Kodiak is looking at another part of the disease.

IL-6 is an inflammatory signaling protein that can contribute to inflammation, problems with blood vessel function and disruption of the blood-retinal barrier. Increased levels of IL-6 have been found in the eyes of patients with DME.

KSI-501 is designed to block both pathways at the same time. The company believes this could provide better control of retinal fluid and potentially improve visual outcomes compared with blocking VEGF alone.

How KSI-501 Is Designed to Work

KSI-501 combines two different components in one intravitreal treatment.

The first component is a VEGF-trap designed to block VEGF activity. This is intended to reduce abnormal vascular permeability and blood vessel growth.

The second component is an antibody designed to block IL-6 signaling. This is intended to reduce inflammatory activity and help normalize the blood-retinal barrier.

The treatment is built using Kodiak's ABC Platform, which is designed to extend the time the medicine remains active inside the eye.

The platform has a reported intraocular half-life of around 20 days. Kodiak is using this technology to explore whether KSI-501 can provide longer-lasting treatment effects while reducing injection frequency.

What Is the ALTO Phase 3 Trial?

The ALTO trial, also known as Study KSMP002-S1, is a global, multicenter, randomized, double-masked Phase 3 study.

It will compare KSI-501 with aflibercept, an established anti-VEGF treatment.

Approximately 910 patients with visual impairment caused by center-involved diabetic macular edema are expected to participate.

The study includes both patients who have never received treatment and patients who have previously received treatment for DME.

Participants will be divided into three treatment groups.

KSI-501 Every Eight Weeks

The first group will receive 5 mg of KSI-501 every eight weeks after six monthly loading doses.

Patients will also be assessed monthly to determine whether individualized dosing is needed.

KSI-501 With Individualized Dosing

The second group will receive 5 mg of KSI-501 after six monthly loading doses.

After the loading period, dosing intervals can range from every four weeks to every 24 weeks, depending on the patient's response.

This part of the study is designed to test whether some patients can maintain treatment benefits with longer intervals between injections.

Aflibercept Comparison Group

The third group will receive 2 mg of aflibercept every eight weeks after five monthly loading doses.

This group will provide the active comparison needed to determine whether KSI-501 can outperform standard anti-VEGF treatment.

What Will the Researchers Measure?

The main goal of the ALTO trial is to measure the change in best-corrected visual acuity from the beginning of the study to the average result at Weeks 48 and 52.

Researchers will also look at changes in diabetic retinopathy severity.

The key secondary endpoint is the percentage of patients who achieve an improvement of at least two steps on the Diabetic Retinopathy Severity Scale at Week 48.

Other measurements will look at retinal anatomy, visual function, treatment burden, durability and safety.

Patients will be treated and followed for approximately 96 weeks.

Why DME Still Needs Better Treatment Options

Diabetic macular edema occurs when blood vessels in the retina become damaged and leak fluid into the macula, the part of the retina responsible for detailed central vision.

VEGF plays an important role in this process, which is why anti-VEGF treatments have become a major part of DME care.

However, treatment does not work equally well for everyone.

Some patients continue to have retinal swelling or do not recover their vision completely. Others need repeated injections over long periods, creating an ongoing treatment burden.

This is why researchers are exploring additional biological pathways such as IL-6.

Earlier Studies Support the Dual-Target Approach

Kodiak's development of KSI-501 follows earlier clinical research looking at IL-6 and VEGF as separate and combined treatment targets.

The Phase 2 ALLUVIUM study found that blocking IL-6 alone could produce anatomical and functional improvements in some patients with DME.

The Phase 2 BARDENAS study also provided evidence that blocking both VEGF and IL-6 could potentially produce stronger effects than targeting either pathway alone.

These findings provide part of the scientific basis for testing KSI-501 in a larger Phase 3 study.

What Has Been Seen With KSI-501 So Far?

In preclinical studies, KSI-501 demonstrated activity against both VEGF and IL-6.

The treatment also showed an ability to normalize the blood-retinal barrier in preclinical models.

These findings have led Kodiak to investigate whether the dual-target approach could potentially provide more sustained control of retinal disease.

However, the Phase 3 ALTO trial will be important for determining whether the benefits seen in earlier research translate into meaningful improvements for people with DME.

KSI-501 Is Also Being Studied in Wet AMD

ALTO is not the only late-stage study for KSI-501.

Kodiak is also evaluating KSI-501 in the Phase 3 DAYBREAK study for wet age-related macular degeneration.

The DAYBREAK study has completed enrollment, and Kodiak expects to report topline one-year data in September 2026.

The company is using an enhanced 50 mg/mL formulation of KSI-501 in DAYBREAK. The formulation contains both conjugated and unconjugated antibody components and is designed to balance rapid treatment activity with longer durability.

Kodiak's Other Retina Programs

KSI-501 is part of a broader late-stage pipeline at Kodiak Sciences.

The company is also developing Zenkuda (tarcocimab tedromer), which has a BLA-ready profile for diabetic retinopathy, retinal vein occlusion and wet AMD.

Zenkuda and KSI-501 are being developed for retinal vascular diseases where anti-VEGF medicines represent a major treatment market.

Kodiak is also developing KSI-101 for macular edema secondary to inflammation, or MESI.

KSI-101 is being evaluated in two Phase 3 studies, PEAK and PINNACLE. Topline data from the first pivotal analysis of the PEAK study are expected in December 2026, while data from the second analysis covering PEAK and PINNACLE are expected in the second quarter of 2027.

What Comes Next for ALTO

The ALTO trial is now enrolling patients across global study sites.

The study will provide a direct test of whether targeting IL-6 and VEGF together can deliver better outcomes than VEGF inhibition alone in diabetic macular edema.

The trial will also examine whether KSI-501 can support longer dosing intervals, including individualized treatment schedules extending to as long as six months.

Kodiak is continuing to advance KSI-501 through its Phase 3 development program while also preparing for the upcoming DAYBREAK data readout in wet AMD.