An investigational anti-VEGF biologic designed for long-interval dosing without compromising immediacy

---

Tarcocimab is our most advanced program. We have important learnings from six pivotal studies across four major retinal diseases and maintain our conviction that tarcocimab could be an important medicine. With tarcocimab’s signature durability and safety record, as demonstrated in multiple studies, we believe tarcocimab could be differentiated in the market as a longest-acting biologic based on its ABC Platform design.

Our objective is to finish the clinical development program and enable the marketing application. We intend to do this using the enhanced formulation of conjugated and unconjugated forms that we believe balances towards durability without compromising immediacy.

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.

Our Phase 3 studies across high-prevalence retinal diseases

---

Three Phase 3 studies complete with compelling durability demonstrated in diabetic retinopathy, retinal vein occlusion and wet age-related macular degeneration.

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. The enhanced formulation of conjugated and unconjugated forms is designed to balance toward durability without compromising immediacy.

Results from our Phase 3 clinical studies

---

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.

Tarcocimab tedromer and the ABC Platform are purposefully designed for increased durability

---

Tarcocimab tedromer

Extended intraocular half-life High formulation strength Enhanced commercial-scale formulation

ABC Platform

Focuses conjugate on its target and prevents non-specific interactions Can slip through crowded or tight areas, like retina tissue, that would otherwise impede it Able to penetrate tissues due to its high lubricity Uses water to bind to targets with high affinity and specificity

See how tarcocimab compares to today’s anti-VEGF molecules →

Learn more about the science of our ABC Platform →

Tarcocimab tedromer aims to maintain therapeutic activity for longer.

First-in-class for high-prevalence retinal vascular diseases

An investigational bispecific biologic designed to address the opportunity for improved efficacy with extended durability by targeting retinal inflammation and vascular permeability

---

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, our second investigational medicine built on our Antibody Biopolymer Conjugate (ABC) platform, 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

---

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 →

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

---

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

---

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

Following Phase 1 results, we plan to advance KSI-501 into a Phase 3 study in wet AMD

---

Our Phase 1 study in DME, a disease known to have high levels of cytokine-mediated microvascular inflammation in addition to VEGF-mediated vascular permeability, is now complete.

We believe the Phase 1 study results support further clinical development of the KSI-501 program in high-prevalence retinal vascular diseases, such as wet AMD. 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.

We have advanced KSI-501 into the Phase 3 DAYBREAK study to evaluate its efficacy and safety in wet AMD.

KSI-501 contains three tiers of innovation

First-in-class for macular edema secondary to inflammation

A high-strength bispecific protein being developed for the treatment of macular edema secondary to inflammation for which no approved intravitreal biologic therapies exist today

---

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 an investigational and 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 retinal inflammatory disease have limited treatment options today

---

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.

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

---

It has been demonstrated that 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. Consequently, 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

---

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

---

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

---

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