Slide 1: Unmet needs in clinical endpoints and therapeutics for retinal diseases: challenges and innovations
THE OPHTHALMOLOGY MEDICINES COMPANY Unmet needs in clinical endpoints and therapeutics for retinal diseases: challenges and innovations Glaucoma and retinal ganglion cell neuroprotection as a case study
Slide 2: Forward Looking Statements
Forward Looking Statements This release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-looking statements are not based o
Slide 3: Chemistry meets ophthalmology
C h e m is t r y m e e t s o p h t h a lm o lo g y Frank Meng, PhD Jing Ren, PhD Dolly Chang, MD, MPH, PhD Director, Chemistry Discovery Senior Principial Scientist Kodiak Sciences Kodiak Sciences Chief Scientific Officer Kodiak Sciences 3
Slide 4: Glaucoma is a group of progressive optic neuropathies characterized by RGC degeneration
Glaucoma is a group of progressive optic neuropathies characterized by retinal ganglion cell (RGC) degeneration and optic nerve (ON) damage Glaucoma is characterized by RGC degeneration In the clinic, glaucoma progression is tracked using and changes in the optic nerve head (its axons) OCT (structur
Slide 5: Glaucoma is an optic neuropathy driven by neuroinflammation—IOP reduction alone is insufficient
Glaucoma is an optic neuropathy driven by neuroinflammation— IOP reduction alone is insufficient • Historically, glaucoma was thought to occur Recent studies show that neuroinflammation is due to elevated IOP the key driver of optic neuropathy in glaucoma2 ‒ Raised IOP was thought to inflict damage
Slide 6: Memantine experience highlights the difficulty in conducting neuroprotection studies
However, memantine experience highlights the difficulty in conducting neuroprotection studies Two phase 3 trials (n=2298); primary endpoint-visual field progression over 48 months, with decade-long duration Key challenges: • Slow and prolonged disease course • Variable progression rates among patien
Slide 7: Can adequate and well controlled trials be designed to study glaucoma neuroprotection?
Can adequate and well controlled trials be designed to study glaucoma neuroprotection? FDA guidelines for an adequate and well controlled trial: Study design permits Minimize bias on part of Method of assessment is valid comparison subjects, observers and well defined and reliable analysts Comparato
Slide 8: Achieving clinically meaningful and approvable endpoints in glaucoma neuroprotection is challenging today
Achieving clinically meaningful and approvable endpoints in glaucoma neuroprotection is challenging today Glaucoma clinical endpoints Currently studied • Nerve fiber loss and visual field are the two clinically meaningful endpoints in Prevention of nerve fiber layer No glaucoma neuroprotection thinn
Slide 9: Old thinking: neuroprotection takes a long time to measure
Old thinking: neuroprotection takes a long time to measure Glaucoma progression 90 Neuroprotection Untreated 80 Visual field index 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 Years Illustrative only 9
Slide 10: New thinking: improving clinical trial endpoints in glaucoma neuroprotection
New thinking: improving clinical trial endpoints in glaucoma neuroprotection More frequent testing to Greater sensitivity for Early activity biomarkers minimize visual field variability detecting retinal ganglion cell (RGC) losses Neurofilament light chain (NFL), a neurodegeneration biomarker, is el
Slide 11: New thinking: reducing the sample size by selecting fast progressors
New thinking: reducing the sample size by selecting fast progressors Fast progressors have a higher likelihood of Six-month run-in predicts future meeting FDA event criteria progression—feasible for clinical trials • Eyes with faster progression are much more likely to develop a clinical endpoint: 9
Slide 12: Remaining challenges in developing a glaucoma neuroprotection drug
Remaining challenges in developing a glaucoma neuroprotection drug • Standard of care constraints: Withdrawing IOP-lowering drops is unethical, so new therapies must demonstrate neuroprotection on top of existing treatments • Multifactorial disease: Glaucoma optic neuropathy involves multiple pathog
Slide 13: Applying the ABCD Platform to Glaucoma
Applying the ABCD Platform to Glaucoma 13
Slide 14: Kodiak's ABCD Platform is designed for targeted, high drug loading, multi-specific modulation
Kodiak’s ABCD Platform is designed for targeted, high drug loading, multi-specific and tailored modulation of biological pathways Antibody Biopolymer Conjugate Drug (“ABCD”): Conjugates of diverse APIs +/- a biologic A product platform enabling multi-mechanism therapies Target both intracellular and
Slide 15: The ABCD Platform is modular and each component can be customized
The ABCD Platform is modular and each component can be customized to fit a specific therapeutic need 15
Slide 16: A single molecule designed to target NLRP3 and IOP simultaneously
A single molecule designed to target NLRP3, the driver of neuroinflammation that causes optic neuropathy and elevated IOP simultaneously Glaucoma “Duet”: Biopolymer with 2 Small Molecules NLRP3 inhibitor + IOP lowering agent Disease Modifying NLRP3 Inhibitor IOP Lowering Small Molecule Targets the u
Slide 17: Tunable pH releasable linkers for intravitreal uses
Tunable pH releasable linkers for intravitreal uses Class 1: Cyclization-Release Class 2: Eliminative Release CP2 Linker X CP2 Linker CO 2 X Drug Drug X X CP2 Drug CP2 Drug CO2 • Neutral-pH self-immolative linker for IVT ‒ The vitreal environment has near-neutral pH and low enzyme levels; therefore,
Slide 18: NLRP3 Small Molecule Development for Ocular Delivery
NLRP3 Small Molecule Development for Ocular Delivery 18
Slide 19: The NLRP3 inflammasome complex is a key driver of neuroinflammation that results in optic neuropathy
The NLRP3 inflammasome complex is a key driver of neuroinflammation that results in optic neuropathy The NLRP3 inflammasome drives retinal ganglion cell (RGC) degeneration and axon loss1 • First, stress to the optic nerve head activates the NF-кB pathway, upregulating NLRP3 and the production of pro
Slide 20: Evidence from animal models support NLRP3 inflammasome driving optic neuropathy
Evidence from animal models support NLRP3 inflammasome driving optic neuropathy, as evident by RGC degeneration and axon loss • Following an optic nerve crush (pONC), NLRP3 was upregulated in retinal microglial cells. Activation of NLRP3-ASC inflammasome led to the up-regulation of caspase-1 and IL-
Slide 21: Inhibiting NLRP3 has demonstrated the potential to modulate the trabecular meshwork and lower IOP
Inhibiting NLRP3 has demonstrated the potential to modulate the trabecular meshwork and lower IOP • The trabecular meshwork (TM) plays a crucial role in maintaining the aqueous outflow pathway NLRP3, caspase- 1 and IL1β mRNA Preclinical studies demonstrated that levels are inhibiting NLRP3/caspase-1
Slide 22: Considerations for small molecule NLRP3 inhibitors developed for intra-ocular delivery
Considerations for small molecule NLRP3 inhibitors developed for intra- ocular delivery • Across both series, we have multiple examples achieving single-digit nM IC50 in the THP-1 cell IL-1β release assay. • Conjugation handle: ‒ Substitutions on the scaffold end provide a versatile handle for conju
Slide 23: Kodiak's novel NLRP3 inhibitor candidates decrease IL-1β production in preclinical studies
Kodiak’s novel small molecule NLRP3 inhibitor candidates decrease IL-1β production and reduce inflammasome complex formation in preclinical studies NLRP3 inhibitors decrease NLRP3 inhibitors reduce Inhibitors directly affect macrophage IL-1β inflammasome complex formation NLRP3 molecular production
Slide 24: Data from tarcocimab, Kodiak's lead ABCD Platform-Based Medicine in Clinic
Data from tarcocimab, Kodiak’s lead ABCD Platform- Based Medicine in Clinic 24
Slide 25: Challenges in intracellular NLRP3 inhibition: limitations of small molecule delivery
Challenges in intracellular NLRP3 inhibition: limitations of small molecule delivery to retinal and optic nerve targets using today’s technology Limitations of small molecule delivery What if we can create an intravitreally injected small molecule that does not clear the eye quickly? Eye drops • The
Slide 26: Empowered for durability, Kodiak's high molecular weight ABCD Platform
Empowered for durability, Kodiak’s high molecular weight ABCD Platform offers a unique approach to overcome the limitations of small molecule delivery to the eye ABCD Platform 950 kDa 1000 kDa ABCD: Antibody Biopolymer Conjugate Drug 26
Slide 27: Tarcocimab and the ABCD Platform's high molecular weight increases its human ocular half-life
Tarcocimab and the ABCD Platform’s high molecular weight increases its human ocular half-life, extending its therapeutic benefit in the eye Each dot represents the ocular half-life from one individual patient. Blue dots are tarcocimab from the Phase 1b study of tarcocimab in patients with wet AMD, D
Slide 28: Tarcocimab consistently demonstrated extended durability across its pivotal studies
Tarcocimab consistently demonstrated extended durability in multiple retinal vascular diseases across its pivotal studies • Durability remains a key ~60% on 5-month unmet need in retinal vascular dosing in wet AMD diseases • Tarcocimab and the ABCD Platform demonstrated 100% on 6- extended durabilit
Slide 29: Biopolymer selection for glaucoma duet: similar size to tarcocimab
Biopolymer selection for glaucoma duet: choosing a biopolymer with similar size to that used in tarcocimab, demonstrating comparable ocular half-life and pharmacokinetics Biopolymer Alone Biopolymer + Antibody Ocular Ocular PK ofPKBiopolymer in Rabbits Ocular PK of Tarcocimab in Rabbits of Biopolym
Slide 30: ABCD Platform-based glaucoma duet is designed to address 4 key attributes
In summary, ABCD Platform-based glaucoma “duet” is designed to address 4 key attributes needed in a next-generation glaucoma therapy Design attributes of the ABCD Platform-based glaucoma “duet” Neuroprotective • Glaucoma is an optic neuropathy driven by neuroinflammation • The NLRP3 inhibitor target
Slide 31: VETi: Kodiak's digital health innovation for trials and commercial use
VETi Kodiak’s digital health innovation for trials and commercial use high accuracy, frequent testing, patient engagement Retinal images VETi + tarcocimab by VETi for home monitoring + Ophthalmology Neuro/Cardio Consumer Government Fluid Analysis DRSS Scoring Metabolic Blood Oxygen Train Your Visual
Slide 32: Thank You
THANK YOU KODIAK