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Inhaled mRNA-IL-1Ra pulse therapy — computational analysis (comp-033)

Verdict: RED on the systemic-anakinra-equivalent gate at currently-feasible inhaled mRNA doses (4–24 mg per administration). The verdict does not close the modality — three honest paths forward keep the chassis-pending entry chassis-pending-interventions.md §4 active.

Dose-AUC headline

Monte Carlo n=20,000 over priors anchored on Translate Bio MRT5005 + Arcturus ARCT-032 disclosed clinical doses, BNT162b2 plasma-protein detection, Patton & Byron alveolar→systemic transit, and Kineret PK. Median predicted plasma Cmax 0.025 µg/mL [5th–95th pct 0.002–0.28] vs anakinra benchmark 1.5 µg/mL — median ratio 2% of anakinra. Reverse-dose calculation: ~195 mg mRNA needed for median 0.5 µg/mL Cmax (⅓ anakinra); ~585 mg for full anakinra-equivalent. Both 8–25× above the highest currently-disclosed inhaled-mRNA clinical dose (24 mg). Top sensitivity driver: translation efficiency mass ratio (ρ = +0.78).

Three paths forward (the chassis-pending entry stays open)

  1. Repeat dosing within a single flare — 2–4 nebulizer administrations per 24h plausibly accumulate to therapeutic AUC without requiring single-dose breakthroughs. Not modeled quantitatively here; warrants a follow-up comp-NNN AUC-accumulation analysis.
  2. Intra-articular mRNA-IL-1Ra as a different chassis for the same target. Local concentration at the affected joint bypasses systemic dilution that dominates the inhaled math; sister architecture to the comp-035 intra-articular uricase + catalase work. Already flagged as 🟡 cell in delivery-route-matrix.md (RNA platforms × intra-articular).
  3. Sub-anakinra exposure may still be therapeutically meaningful. Anakinra's trough (Cmin) is 0.05 µg/mL and the drug retains efficacy at that exposure; the upper-decile prior in this model (Cmax 0.28 µg/mL sustained over 48h) reaches comparable AUC to anakinra trough-band exposure. The RED verdict is specifically against full anakinra Cmax matching, not against any therapeutic effect.

Construct-design priors

m1Psi (Karikó–Weissman) chemistry; human alpha-globin 5'UTR + truncated alpha-globin / mtRNR1 3'UTR for transient expression matching the 24–48h flare window; 80–120 nt polyA; native IL-1Ra signal peptide (alveolar type II pneumocytes are highly secretory). LNP class ALC-0315 / SM-102 / Acuitas LP-01 with nebulization-stability screen. Vibrating-mesh nebulizer for POC; DPI for commercial product.

Economic comparison (holds independently of dose-feasibility)

Cost-per-flare at scale: $2 (low) / $18 (central) / $120 (high). Annual cost at 5–10 flares/yr: $10–1,200. Canakinumab benchmark: $105K–300K/yr. Cost ratio 50–3,000× in favor of inhaled mRNA-IL-1Ra approach — dominated by mRNA-LNP scale economics, robust across all dose-feasibility scenarios.

Partner landscape — 15 candidates, 4 Tier A

Tier A (active inhaled-mRNA clinical/preclinical programs, 4): Arcturus Therapeutics (LUNAR-CF / ARCT-032, Phase 2); ReCode Therapeutics (RCT2100 + SORT-LNP, Phase 1); Ethris (SNIM-RNA / AstraZeneca, preclinical); Sanofi (legacy Translate Bio MRT5005 platform). Tier B (7 CDMOs): CordenPharma, Aldevron/Danaher, Lonza, Recipharm (inhalation devices), Acuitas (LNP IP), Precision NanoSystems, TriLink/Maravai. Tier C (4 academic labs): Mitchell (UPenn), Sahay (OSU), Anderson (MIT), Siegwart (UTSW — SORT-LNP origin).

Recommended first contacts: Arcturus, ReCode, Siegwart Lab UTSW, Mitchell Lab UPenn.

Implication for the platform

Chassis-pending entry stays open. Discovery-engine handoff package (target validation + construct-design priors + dose math + economic argument + partner shortlist) is shippable now — RED on systemic-equivalent reframes the partner conversation as "this chassis needs a repeat-dose protocol or route pivot, here's the math," not "this won't work." The 50–3,000× cost edge vs canakinumab is what makes the partner conversation worth having.

Cross-references

comp-033 reproducible analysis | chassis-pending-interventions.md §4 | etc/open-enzyme-vision.md §10 "temporal stack" | modality-chokepoint-matrix.md | delivery-route-matrix.md