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Weekly Biotech Watchlist: KDO (Tarcocimab), KZIA (Paxalisib)

Linda
Linda ·
PD-1, IL-2

Executive Summary

This watchlist highlights two upcoming late-stage and early-stage clinical catalysts across ophthalmology and oncology, spanning Phase 3 and Phase 1b development. Using a probability-weighted framework that integrates historical phase-transition base rates with mechanism validation, cross-indication learnings, and trial-level execution risk, we estimate the following probabilities of success:

  • KOD (Tarcocimab tedromer, Diabetic Retinopathy Phase 3): ~50–65%
    A validated anti-VEGF mechanism and highly compelling interim efficacy support above-average late-stage odds, partially offset by platform-level safety overhang from prior retinal indications.

  • KZIA (Paxalisib, Advanced TNBC Phase 1b): ~45–60%
    Meaningfully above historical PI3K/mTOR base rates due to unusually strong early efficacy signals and mechanistic differentiation, though still constrained by class-level attrition and limited sample size.

KOD (Kodiak Sciences) — Tarcocimab Tedromer

  • Indication: Diabetic Retinopathy
  • Stage: Phase 3
  • Estimated Probability of Success: ~50–65%
  • Relative Positioning: Above Average for Retinal Phase 3 Assets

Baseline Prior (Anti-VEGF in DR, Phase 3): ≈60%

  • Anti-VEGF therapy is a highly validated modality in diabetic retinopathy and adjacent retinal diseases. Historically, approximately three out of five anti-VEGF agents entering Phase 3 for DR/DME have ultimately achieved FDA approval, implying an agent-level probability of success around ~60%.
  • This baseline appropriately reflects program-level risk, incorporating not only biological validation but also late-stage execution and safety considerations.

Negative Modifiers — Cross-Indication Failures & Safety Overhang

  • Despite the favorable modality precedent, tarcocimab carries material downside risk driven by its prior clinical history. The molecule failed in a Phase 2/3 wet AMD trial and demonstrated higher intraocular inflammation relative to aflibercept.
  • More critically, the Phase 3 GLEAM/GLEAMER DME programs were discontinued due to lack of efficacy and an unexpected increase in cataract incidence.
  • These late-stage failures in closely related retinal indications establish a non-trivial safety and durability risk, raising the possibility that similar issues could emerge in DR with longer exposure or broader patient enrollment.

Positive Modifiers — Compelling Phase 3 Efficacy & Dosing Differentiation

  • Offsetting these concerns is exceptionally strong efficacy observed in the target indication. The GLOW1 interim analysis demonstrated a 41.1% response rate versus 1.4% for sham (p < 0.0001), representing a large and clinically convincing treatment effect.
  • The validated VEGF-A mechanism materially reduces biological risk, while the tedromer-enabled 6-month dosing interval offers meaningful clinical differentiation by addressing treatment burden—a key adoption driver in DR.

Collectively, these factors support a probability of success above that of a typical late-stage retinal asset, albeit capped by unresolved platform-level safety risk.

KZIA (Kazia Therapeutics) — Paxalisib

  • Indication: Advanced Triple-Negative Breast Cancer
  • Stage: Phase 1b
  • Estimated Probability of Success: ~45–60%
  • Relative Positioning: Above PI3K/mTOR Class Averages

Baseline Prior (PI3K/mTOR Inhibitors in TNBC, Phase 1b): ≈25%

  • PI3K/mTOR inhibitors in breast cancer have historically exhibited extremely high attrition. Among approximately 19 disclosed programs, only everolimus achieved approval—and exclusively in HR+ disease.
  • With roughly 70% Phase II failure rates and the intrinsic resistance of TNBC to this pathway, a conservative baseline probability of success for a Phase 1b TNBC program is set at ~25%.

Negative Modifiers — Class-Level Attrition & Data Limitations

  • The PI3K/mTOR class carries a >95% failure rate from Phase I to approval in breast cancer, with prior examples (e.g., buparlisib) underscoring the persistent toxicity–efficacy trade-off.
  • In addition, current efficacy signals for paxalisib are derived from a very small cohort (n=6), introducing meaningful uncertainty related to selection bias, durability, and statistical robustness.

Positive Modifiers — Unusually Strong Early Signals & Mechanistic Differentiation

  • Paxalisib demonstrates atypically strong early clinical activity for the class, including deep tumor regressions, an immune-complete response, and CTC reductions in most evaluable patients.
  • Mechanistically, it is differentiated as the only reported brain-penetrant PI3K/mTOR inhibitor, expanding its therapeutic relevance in metastatic disease.
  • The program is being evaluated in a modern pembrolizumab-based combination strategy, aligning with current TNBC treatment paradigms, while an established monotherapy safety database (>86 patients) reduces incremental safety uncertainty.

These factors collectively justify a probability of success meaningfully above historical class base rates, though still constrained by early-stage data maturity.

Disclosure: All analysis is conducted by Noah. This content is for informational purposes only and does not constitute investment or medical advice.