STRC Research

STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23

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STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23

TL;DR. 5×5 grid over KD_TMEM145 ∈ [10 nM, 10 μM] × KD_WH2_FACTIN ∈ [1 μM, 1 mM]. Therapeutic window (f ≥ 0.3 HTC coupling, 22 dB ABR rescue) reachable on 80% of grid (56% single-dose tolerable ≤ 5 mg + 24% marginal dose 5-20 mg). FAIL only at WH2 Kd ≥ 1 mM (Tβ4 analog floor) — G-actin toxicity ceiling hit before f=0.3 achievable. Strategic finding: WH2 Kd dominates, TMEM145 Kd is secondary. Reorders wet-lab priority: Phase 2c WH2 bundling becomes gate #1; TMEM145 SPR/BLI is now gate #2 (ipSAE already placed it in operable band). A held, Mech 4 held, Deliv 3 held. Not quite S-robust (70% PASS threshold needed, got 56%) but reachable-80% decent; S promotion still requires WH2 Kd wet-lab narrowing.

Model

Simple two-site independent-binding functional form for synthetic HTC formation:

f = θ_T × θ_W
θ_T = [L] / (KD_TMEM145 + [L])   — TMEM145 anchor occupancy
θ_W = [L] / (KD_WH2_FACTIN + [L]) — F-actin hook occupancy

For each (Kd_T, Kd_W) grid point, solve minimum [L] for f ≥ 0.3 (conservative, 22 dB ABR per Tobin 2019 bundle Hopf coupling) and f ≥ 0.6 (stretch, 30 dB). Then back out intratympanic dose via Phase 4e 2-compartment PKPD (Dhanasingh 2021 volume, Salt & Plontke 2018 clearance, Salt & Ma 2001 RWM). Flag PASS (dose ≤ 5 mg — AM-101 intratympanic precedent) / MARGINAL (5-20 mg) / FAIL (>20 mg or [L] > 100 μM toxic ceiling for G-actin depletion).

Kd grid rationale

ParameterLowHighSource
KD_TMEM14510 nM10 μMipSAE 0.591 places Ultra-Mini × TMEM145 GOLD in Calcineurin family (NFAT-CnB 100 nM - 2 μM). Range adds 10× margin each side. See STRC ipSAE Cross-Complex Reassessment 2026-04-23.
KD_WH2_FACTIN1 μM1 mMOptimistic current model 5 μM (25× weaker than WH2 × G-actin); Tβ4 F-actin analog floor 5-10 mM. Range covers the full literature-plausible span. See STRC h09 Parameter Provenance Audit 2026-04-23.

Results

f ≥ 0.3 (22 dB ABR rescue) — conservative target

Kd_T\Kd_W          1μM        5μM       50μM    200μM      1mM
   0.01μM         PASS       PASS       PASS  MARGINAL  FAIL_toxic
    0.1μM         PASS       PASS       PASS  MARGINAL  FAIL_toxic
    0.5μM         PASS       PASS       PASS  MARGINAL  FAIL_toxic
      2μM         PASS       PASS       PASS  MARGINAL  FAIL_toxic
     10μM         PASS       PASS   MARGINAL  MARGINAL  FAIL_toxic
  • PASS 56%, MARGINAL 24%, FAIL 20%. Reachable 80%.
  • FAIL column is exclusively at WH2 Kd = 1 mM (close to Tβ4 floor).
  • TMEM145 Kd matters only at the weakest corner (10 μM TMEM145 × 50 μM WH2 slips from PASS to MARGINAL).

f ≥ 0.6 (30 dB ABR rescue) — stretch target

PASS 40%, MARGINAL 20%, FAIL 40%. Reachable 60%. Stretch target less robust as expected (quadratic in occupancy).

Key strategic inference

WH2 × F-actin Kd is the load-bearing parameter. The pass/fail geometry is almost column-invariant (i.e., determined by WH2 row independent of TMEM145). This reorders the wet-lab gate ordering:

Previous priorityRationaleNew priority
1. STRC × TMEM145 SPR/BLIGate 3 placeholder→ 2 (ipSAE already places in operable band 10 nM - 10 μM; entire TMEM145 row PASSes or MARGINAL’es regardless of exact Kd)
2. WH2 × F-actin bundling (Phase 2c HEK293 GFP-actin confocal)Gate 2 placeholder→ 1 (determines whether therapy lives in PASS zone [WH2 Kd < 50 μM] or FAIL zone [WH2 Kd > 500 μM])

What this doesn’t resolve

  • If WH2 × F-actin Kd is actually in the 1 mM range (Tβ4-like), therapy FAILS: can’t hit f=0.3 before toxic G-actin depletion. Wet-lab must rule this out.
  • Toxic ceiling at 100 μM perilymph is itself model-dependent — G-actin pool depletion assumed to dominate at that concentration; could be higher or lower depending on actual G-actin turnover under drug. Phase 4d supports 100 μM ceiling but hasn’t been wet-lab validated.
  • Model assumes independent binding at HTC. Real HTC geometry may have cooperativity (+) or anti-cooperativity (−) that shifts the f = θ_T × θ_W relationship.

Promotion verdict

A held. Verdict string: A_hold_multi_dose_ok — therapy is reachable on 80% of plausible Kd space, but only 56% single-dose tolerable. S threshold was 70% PASS single-dose. Promotion argument still requires wet-lab Kd narrowing — specifically WH2 bundling assay.

Ranking delta

  • #9 (h09) Synthetic Peptide Hydrogel HTC: A held. Mech 4 held. Deliv 3 held. Next-step reordered: Phase 2c WH2 bundling (HEK293 GFP-actin confocal) is now the promotion-gate #1, ahead of TMEM145 SPR/BLI. Sensitivity sweep shows therapy is PASS-reachable across 80% of plausible Kd space but WH2 is the dominant load-bearing parameter. TMEM145 Kd no longer on the critical path (operable over entire ipSAE-placed band).

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