Kodiak Sciences Inc. recently announced that the first patients have been enrolled in the global phase 3 ALTO trial evaluating KSI-501 in patients with diabetic macular edema (DME).
Give me a refresher on Kodiak Sciences.
The pre-commercial, retina-focused biotechnology company currently has three candidates in development for retinal vascular diseases:
- Zenkuda (tarcocimab tedromer 5 mg)
- Indications: diabetic retinopathy (DR), wet age-related macular degeneration (AMD), and retinal vein occlusion (RVO)
- KSI-501 (tabirafusp tedromer 5 mg; the topic of today’s story)
- Indications: wet AMD and DME
- KSI-101 (tabirafusp alfa 100 mg/mL [high strength formula])
- Indication: macular edema secondary to inflammation (MESI)
And what scientific approach are these assets built on?
That would be the antibody biopolymer conjugate (ABC) platform, designed to enable multi-mechanism therapies with durability and to block all vascular endothelial growth factor (VEGF)-A isoforms.
- What it does: Combines a targeting antibody (which binds VEGF in the eye) to a large, water-soluble biopolymer (attached to that antibody) to create a single, long-lasting therapeutic.
See a step-by-step (and 3-D) look at this process.
Now, didn’t we recently hear from Kodiak?
Indeed. In March the company reported positive topline data from the phase 3 GLOW2 trial (NCT06270836) evaluating Zenkuda (tarcocimab tedromer) for DR treatment.
A quick refresher on that data: GLOW2 met its primary endpoint; by Week 48, with 62.5% of Zenkuda-treated patients achieving a ≥2-step improvement in DRSS score (versus 3.3% in the sham group; p< 0.0001).
- Also worth keeping in mind: Kodiak rebooted the tarcocimab tedromer clinical program in November 2023—just months after initially halting its development for DME in August 2023.
- The reason: a promising data readout from the phase 3 GLOW study (NCT05066230) for a different retinal indication: DR.
Got it. Next: Let’s zero in on KSI-501.
The investigational, first-in-class bispecific therapy is designed to potently inhibit two complementary pathways implicated in retinal vascular disease:
- Interleukin-6 (IL-6)-mediated inflammation
- Vascular endothelial growth factor (VEGF)-mediated vascular permeability and neovascularization
And as with other candidates in Kodiak’s pipeline: KSI-501 features the ABC platform, enabling its signature 20-day intraocular half-life that’s intended to support sustained intraocular activity and extended durability.
How has it performed in previous trials?
In preclinical models, KSI-501 was shown to be a potent inhibitor of both VEGF and IL-6 and to normalize the blood-retinal barrier—opening the possibility for it to be a disease-modifying therapy for retinal vascular diseases.
Plus, data from the phase 2 ALLUVIUM study (NCT05151731) “demonstrated that IL-6 inhibition alone can lead to clinically meaningful functional and anatomical benefits in DME patients,” according to Margaret Chang, MD, MS, co-director of Clinical Research at Retina Consultants Medical Group and a key principal investigator of several late-stage trials at Kodiak.
- Meaning: This provides evidence that the IL-6 pathway is biologically active in diabetic eye disease and operates independently of VEGF-driven pathology.
“Importantly, the recent phase 2 BARDENAS study (NCT05151744) further suggested that dual inhibition of VEGF and IL-6 may offer synergistic effects, with the potential to deliver superior vision gains and improved fluid control versus targeting either pathway alone,” she added.
That brings us to the present: this phase 3 DME study
Correct. Although. the candidate has actually advanced into two registrational phase 3 trials (DAYBREAK [NCT06556368] and ALTO [NCT07734844] ) for wet AMD and DME, respectively:
- DAYBREAK trial status: enrollment complete
- Features KSI-501’s enhanced 50 mg/mL formulation containing both conjugated and unconjugated antibodies that are intended to balance immediacy and durability.
- ALTO trial status: currently enrolling patients
What else should we know about the ALTO study?
Its design: global, multicenter, randomized, double-masked, active comparator-controlled study
Its purpose: to demonstrate the superiority of bispecific KSI-501 versus monospecific aflibercept 2 mg in patients with visual impairment secondary to center-involved DME.
Its setup: two dosing regimens administered across approximately 910 patients (treatment-naïve or previously treated) randomized 5:3:5 to one of three arms:
- Arm A: KSI-501 5 mg every 8 weeks, with monthly assessment for additional individualized dosing, following 6 monthly loading doses
- Arm B: KSI-501 5 mg on an individualized regimen of every 4 to 24 weeks, following 6 monthly loading doses
- Arm C: Aflibercept 2 mg every 8 weeks, following 5 monthly loading doses
The duration: Patients will be treated and followed for an estimated 96 weeks.
And what will be evaluated?
The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to the average of Week 48 and Week 52.
The secondary endpoint: a 2-step or greater improvement on the Diabetic Retinopathy Severity Scale (DRSS)
So what’s Kodiak expecting from this study’s outcomes??
For that, we’ll refer to CMO J. Pablo Velazquez-Martin, MD, who noted that the study is evaluating:
whether dual inhibition of IL-6 and VEGF translates into meaningful benefit for patients—including the potential for better vision gains and greater fluid control—as well as through Kodiak's ABC biopolymer conjugate platform.
- The potential behind this: superior durability for KS-501.
“Our objective is to characterize efficacy, anatomic response and durability in a single phase 3 program,” he added.
And when can we expect an update?
The ALTO study has an estimated primary completion date of Oct. 31, 2028, so we’ll likely see a data readout before then.
Noted. And in the meantime??
Looking beyond this DME candidate, the phase 2 DAYBREAK study evaluating both Zenkuda and KSI-501 for wet AMD has completed enrollment—and topline data is expected next month.
- Note: The company reports a “BLA (Biologics License Application)-ready profile” for all three of Zenkuda’s indications, so we may be getting movement there soon.
For KSI-101: The phase 3 PEAK and PINNACLE trials (MESI) are actively recruiting, with topline data for the pivotal analysis 1 (PEAK) expected in December 2026 and pivotal analysis 2 (PEAK+PINNACLE) in Q2 2027.
As always, stay tuned!