An investigational anti-VEGF biologic designed
for strong immediacy and high durability

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Tarcocimab is our most advanced program and one successful pivotal study away from a Biologic License Application (BLA) in 3 major retinal vascular diseases.

Tarcocimab is an anti-VEGF Antibody Biopolymer Conjugate (ABC) being developed to provide strong immediacy and high durability. Across multiple studies in high-prevalence retinal vascular diseases, tarcocimab demonstrated consistent 6-month predominant durability and favorable safety. With a flexible 1-month through 6-month label, we believe tarcocimab can be the “mainstay” intravitreal biologic for all patients.

1. Across tarcocimab tedromer pivotal studies for diabetic retinopathy, retinal vein occlusion and wet age-related macular degeneration.
2. According to the product label for aflibercept, high-dose aflibercept, faricimab and ranibizumab.

The enhanced formulation is engineered for immediate and durable VEGF inhibition

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The enhanced formulation of tarcocimab includes unconjugated and conjugated protein. The unconjugated protein is designed to deliver a strong “pulse” of VEGF inhibition and the conjugated protein is designed to persist in the eye to provide sustained disease control.

Our Phase 3 studies across high-prevalence retinal diseases

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Three Phase 3 studies complete in three major retinal diseases. Primary endpoint met and compelling durability demonstrated.

	Study Design	Primary Endpoint	Extended Durability
GLOW1 Study Diabetic Retinopathy	253 patients Tarcocimab Q24W vs sham Superiority study	✓	✓	See Results
BEACON Study Retinal Vein Occlusion	568 patients Tarcocimab Q8W vs aflibercept Q4W	✓	✓	See Results
DAYLIGHT Study Wet Age-Related Macular Degeneration	557 patients Tarcocimab Q4W vs aflibercept Q8W	✓	Not Applicable	See Results

In addition to these studies, tarcocimab was also studied in the Phase 2b/3 DAZZLE study in wet AMD and in the Phase 3 GLEAM and GLIMMER studies in DME. These studies did not meet primary endpoint but did demonstrate strong 5 and 6-month durability in the majority of patients.

Two new Phase 3 studies in process using the enhanced formulation of tarcocimab.

	Study Design	Primary Endpoint	Anticipated Timing
GLOW2 Study Diabetic Retinopathy	250 patients Tarcocimab Q24W Superiority study Uses enhanced 50 mg/mL formulation		Enrollment complete	See Results
DAYBREAK Study Wet Age-Related Macular Degeneration	Designed as a registrational study for both tarcocimab and tabirafusp Tarcocimab objective: assess 6-month durability potential with individualized Q4W-Q24W dosing Tabirafusp objective: explore efficacy potential of bispecific IL-6 and VEGF inhibition in fixed Q8W dosing with additional individualized monthly dosing Uses enhanced 50 mg/mL formulation		Actively Recruiting	See Results

Results from our Phase 3 clinical studies

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Tarcocimab demonstrated differentiated durability in the GLOW1 study in diabetic retinopathy and in the BEACON study in retinal vein occlusion.

GLOW1 Phase 3 study in diabetic retinopathy¹

1. The Phase 3 GLOW1 study is a global, multi-center, randomized pivotal study designed to evaluate the efficacy and safety of tarcocimab in patients with treatment-naïve, moderately severe to severe DR. All patients were randomized to receive either tarcocimab every six months after 3 initiating doses or to receive sham injections.

DRSS: diabetic retinopathy severity scale; DME; diabetic macular edema; PDR; proliferative diabetic retinopathy; ASNV: anterior segment neovascularization; CST; central subfield thickness; BCVA; best corrected visual acuity; NVD: neovascularization of the disc; NVE; neovascularization elsewhere; VH: vitreous hemorrhage; NVG; neovascular glaucoma.
Weighted percentages are based on weighted average of observed estimates across strata using CMH weights. p-values are based on the difference in response rates.

BEACON Phase 3 study in retinal vein occlusion²

2. The Phase 3 BEACON study is a global, multi-center, randomized study designed to evaluate the durability, efficacy and safety of tarcocimab tedromer Q8W vs. aflibercept Q4W in patients with macular edema due to RVO.

First-in-class

An investigational anti-IL-6 and VEGF trap bispecific biologic designed for higher efficacy and higher durability

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KSI-501 is a bispecific Antibody Biopolymer Conjugate (ABC) designed to address two key unmet needs in high-prevalence retinal vascular diseases – higher efficacy and higher durability – by targeting retinal inflammation and vascular permeability simultaneously.

Inflammation has been shown to play a significant role in high-prevalence retinal vascular diseases. However, no treatments exist that concurrently address vascular permeability and inflammation. KSI-501 is designed to inhibit VEGF and IL-6, a pro-inflammatory cytokine and immune growth factor, combining two powerful mechanisms of action to address retinal vascular disease and the underlying inflammatory cascade.

KSI-501 is designed for highly efficient binding to both IL-6 and VEGF

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The anti-permeability effect of VEGF inhibition is the primary effector, with the anti-inflammatory effect of IL-6 inhibition offering the potential for additional clinical benefits.

See electron microscopy image of KSI-501 →

The enhanced formulation is engineered for immediate and durable bispecific inhibition

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The enhanced formulation of KSI-501 includes unconjugated and conjugated protein. The unconjugated protein is designed to deliver a strong “pulse” and the conjugated protein is designed to persist in the eye to provide sustained disease control.

IL-6 levels are significantly elevated in eyes with retinal vascular disease and are implicated in anti-VEGF treatment resistance

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Vitreous IL-6 levels in patients with retinal vascular disease vs. control¹

Aqueous humor IL-6 levels significantly correlate with anti-VEGF treatment response in wet AMD²

2. Adapted from Chalam et al. (2014). Journal of Ophthalmology, Article ID 502174. Mean with SEM plotted.

In pre-clinical studies, dual inhibition of IL-6 and VEGF by KSI-501 show a synergistic effect

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Dual inhibition of VEGF and IL-6 by KSI-501 confers superior normalization of complex tight junction-mediated barrier biology compared to either anti-VEGF or anti-IL-6 monotherapy alone demonstrating the synergistic effect of IL-6 and VEGF dual inhibition on retinal vascular disease.

With dual effect on the blood retinal barrier, KSI-501 holds the potential to be a new disease-modifying therapy.

Inner blood-retinal barrier: leakage from vascular endothelium disruption leads to macular edema and hemorrhage
Outer blood-retinal barrier: RPE integrity prevents choroidal vascularization from invading the retina

Phase 3 DAYBREAK study of KSI-501 in wet AMD is actively enrolling

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KSI-501 is being investigated in the ongoing Phase 3 DAYBREAK study in wet AMD. The DAYBREAK study is designed to explore the efficacy potential of bispecific IL-6 and VEGF inhibition in fixed Q8W with individualized monthly dosing of KSI-501.

In wet AMD, there is preclinical evidence that IL-6 is implicated in the development of choroidal neovascularization and clinical evidence demonstrating that IL-6 is associated with development and progression of AMD, resistance to anti-VEGF treatment in wet AMD, and reactivation of disease by promoting growth of new neovascular membranes.

DAYBREAK follows the encouraging results of the Phase 1 study of KSI-501 in DME, a disease known to have high levels of cytokine-mediated microvascular inflammation in addition to VEGF-mediated vascular permeability.

KSI-501 has three tiers of innovation

First-in-class

An investigational, high-strength bispecific protein to treat macular edema secondary to inflammation for which no approved intravitreal biologic therapies exist today

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In patients with intraocular inflammation, significant vision loss is most commonly a consequence of macular edema. Studies show that inflammation and vascular permeability have a synergistic effect on driving disease progression and vision loss due to macular edema, but there are no approved therapies that target both drivers of disease.

KSI-101 is a high-strength (100 mg/ml) bispecific protein designed to directly target both IL-6-mediated inflammation and edema, and VEGF-mediated vascular permeability. The anti-inflammatory effect of IL-6 inhibition is the primary effector, with the anti-permeability effect of VEGF inhibition having an additive and synergistic effect.

Patients with vision-threatening inflammatory disease have limited treatment options today

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Macular edema is the leading cause of vision loss among uveitis patients, a heterogeneous group of diseases characterized by intraocular inflammation. Many patients with macular edema have persistent disease activity despite treatment and are at risk for vision loss.

In macular edema associated with inflammation there is no standard treatment algorithm and patients are exposed to therapies with limited efficacy and undesirable side effects.

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Studies show that both IL-6 and VEGF play a key role in retinal inflammatory disease

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IL-6 levels are elevated in ocular compartments and in serum in patients with non-infectious uveitis, and further elevated in uveitis patients who have macular edema.

1. Valentincic et al. Molecular Vision 2011; 17: 2003-2010
2. de Boer et al.  Curr Eye Res. 1992;11 Suppl:181-186

In addition, persistent inflammation triggers VEGF upregulation. VEGF levels are found to be elevated in aqueous humor of eyes with uveitis and uveitic macular edema, which can lead to angiogenesis, vascular leakage, and blood-retinal barrier dysfunction.

KSI-101 focuses on a market opportunity outside the established anti-VEGF class

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KSI-101 is being evaluated in the APEX Phase 1b Study and we plan to advance KSI-101 into dual Phase 2b/3 studies in patients with macular edema secondary to inflammation.​

Multi-mechanism, multi-modality targeted biologic for complex retinal and systemic diseases

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Triplet medicines combine the benefits of our Antibody Biopolymer Conjugate (ABC) Platform for long-interval dosing of biologics with a new feature that adds sustained release of 100s of small molecules to target three or more mechanisms of action, enabling treatment of complex, multifactorial diseases.

Designing a new generation of targeted therapy for high-prevalence multifactorial diseases

Our triplet ABC medicines aim to broaden what’s possible with antibody conjugate therapies

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Antibody Drug Conjugate (ADC) therapies are revolutionizing the way cancer is treated today by delivering highly potent cancer-killing agents directly to cancer cells via a targeted antibody. With our ABC triplet medicines, we aim to build on this foundation in notable ways:

ADC Primarily developed to treat cancer today Constrained by its Drug Antibody Ratio (DAR) of up to 8 Limited to using small molecules that are highly potent and cytotoxic with serious side effects Antibody primarily serves as a targeting agent to deliver cytotoxic small molecules to cancer cells

ABC Triplet Medicine Designed for ophthalmic and also systemic diseases such as cancer Designed to provide DARs of 50, 100 and up to 250 by embedding the biopolymer with small molecules Enables the use of mechanistic small molecules rather than cytotoxins Biopolymer can also be stably linked to a protein therapeutic (e.g., antibody) Same durability benefit enabled by the ABC Platform Antibody can be designed to target a cell or a biological pathway