Cascade Pipeline: TARGETING DISEASES DRIVEN BY THE PRESENCE OF HYPOXIA
CPD100: Lead Program In Ophthalmology
CPD100Li: Secondary Program In Oncology
Cascade Development Programs
CPD100 in Wet Age-Related Macular Degeneration (wet AMD)
Executive Summary
- Wet age‑related macular degeneration (wet AMD) develops primarily from hypoxia-driven vascular endothelial growth factor (VEGF) upregulation and secretion by mononuclear phagocytes, leading to abnormal blood vessel growth (neovascularization) and leakage under the retina, rapidly damaging central vision
- Medicare spends >$4B per year on drugs to treat AMD-related neovascularization
- CPD100 is activated under hypoxia to release vinblastine, which exerts dual anti-angiogenic effects:
- Suppression of abnormal blood vessel growth,¹ and
- Reduction of mononuclear phagocytes and other cells that stimulate excess VEGF production²,³
- Suprachoroidal administration of CPD100 has the potential to become the first targeted therapy to selectively inhibit angiogenesis in wet AMD through a dual mechanism of action
Wet AMD: Evolution in the Ageing Eye
About Wet AMD
- ~2M Americans affected; rapid, permanent central vision loss
- Hypoxia → excess VEGF → choroid neovascularization + mononuclear migration → vascular leakage
- Medicare spends >$4B/year on anti VEGF drugs, standard of care
- Current therapies are palliative, not disease modifying
- Multiple blockbuster intravitreal-anti VEGF drugs (Eylea®, Lucentis®, Vabysmo®)
- Strong investor and pharma activity (e.g., EyeBio/Merck $1.3B upfront acquistion)
Limitations of Anti VEGF Therapies
- Require intravitreal injections with limited targeting to the retina and choroid (painful)
- Monthly loading + q2–4 month maintenance
- Do not address hypoxia, direct action on growth of endothelial cells or on VEGF‑producing immune cells
- Risks: retinal tear, hemorrhage, cataract, uveitis, IOP elevation
Source: https://www.drugdiscoverynews.com/a-new-type-of-injection-could-improve-eye-disease-treatment-16458 Illustration by Alisha Vroom
CPD100 Mechanism of Action
- Vinblastine N‑oxide is a prodrug converted to vinblastine (VBL) only in hypoxic tissue
- Endothelial cells highly sensitive to VBL→ rapid shutdown of abnormal vessel growth¹
- Mononuclear phagocytes (M2) reduced → upstream VEGF suppression²,³
- Potential for more durable and more complete disease control
Growth Inhibition of Endothelial Cells Exposed to VBL
Reduction of M2 cells in Tumors Treated with CPD100
CPD100 Mechanism of Action
- Direct access to choroid, the site of pathology
- Minimizes vitreous exposure and systemic toxicity
- FDA‑cleared micro‑injection technology (e.g., Bella-Vue / Uneedle) validated in AMD trials
- Enables safer and more targeted therapy to the choroid
- Growing clinical adoption of suprachoroidal injection
- Easy and reliable to use — 100% user satisfaction; single microneedle length¹⁰
Mentink S – EURETINA 2025
Commercial Opportunity for CPD100 in Wet AMD
- Wet AMD prevalence: ~2M US patients
- CPD100 advantages:
- Directly targets disease source (neovascularization + para-inflammation)
- Potential to improve vision and decrease frequency of administration
- Suprachoroidal administration avoids intravitreal morbidity
- Potential ≥20% market share in mid‑2030s
- Expansion into other indications:
- Predominant Antiangiogenic Effect
- Diabetic macular edema (DME)
- Macular edema following retinal vein occlusion (MEfRVO)
- Predominant Anti-Inflammatory Effect
- Dry AMD – Geographic atrophy
- Prior retinal transplantation in retinitis pigmentosa, AMD, etc.
- Oncology
- Retinoblastoma
- Uveal melanoma (+ Ipilimumab)
CPD100Li in Hypoxia-Prone Tumors
CPD100Li is a liposomal formulation of CPD100 for systemic administration to reverse the effects of a hypoxic microenvironment in cancer.
Supports the foundation of our development of CPD100Li
Efficacy | Safety | Penetration
Potent Anti-Tumor Efficacy
CPD100Li exhibits potent anti-tumor efficacy in established preclinical xenograft models in which hypoxic tumors develop. In the A549 non-small cell lung cancer model, CPD100Li significantly outperformed both cisplatin (treatment control) and unformulated CPD100. CPD100Li is highly effective in the Panc-1 orthotopic pancreatic cancer model, a fast-growing tumor model that is normally resistant to treatment. CPD100Li also showed strong synergy in combination with an anti-CTLA-4 agent in a CT26 colorectal model.
Non-small cell lung cancer solid tumor xenograft
CPD100 dosed at 40 mg/kg (iv) in all on-treatment cohorts
Cisplatin dosed at 2.5 mg/kg
tumor volumes at start of treatment normalized to 100%
Highly aggressive; difficult to treat; extreme hypoxia
CPD100 dosed at 40 mg/kg (iv) in all on-treatment cohorts
Gemcitabine dosed at 100 mg/kg (ip)
tumor volumes at start of treatment normalized to 100%
Summary
- Liposomal formulation enhances activity of unformulated CPD100 in multiple models
- Activity demonstrated with CPD100Li monotherapy
- Strong synergy shown in combination with gemcitabine and an anti-CTLA-4 agent in Panc-1 model and CT26 colorectal model respectively
Improved Safety Profile
We believe CPD100Li’s hypoxia targeted, liposomal formulated profile will offer patients a significantly improved safety profile relative to currently approved chemotherapy agents. CPD100Li has the potential to significantly reduce the side effects that would accompany an equivalent amount of vinblastine thereby improving outcomes in patients with solid tumors.
- CPD100Li has been well tolerated in all in vivo studies conducted to date in mice
- No acute toxicities observed to date (MTD = 40 mg/kg)
- No weight loss in tumor-bearing mice on treatment
- Modest elevations of liver enzymes and hematological markers
- Unformulated CPD100 has >10X greater MTD than vinblastine
Enhanced Penetration of Solid Tumors
CPD100Li has been engineered to enhance tumor penetration with an average particle size of 170 nm, which allows tumor penetration through the aberrant vascular endothelium found in many tumor types. Liposomal formulation also extends the circulation half-life of CPD100 by more than 10-fold. In mouse PK studies, unformulated CPD100 is rapidly cleared with a t1/2 of 0.4 h. By contrast, the t1/2 clearance rate observed with CPD100-Li was 5.5 hrs. The small particle size, combined with extended circulation time, optimize the potential for efficient tumor penetration.
