Status: COMPLETE SBML L3v2 · 0 errors Calibration PASS 96% Holdout PASS 83% V&V 20/21 PASS ASME V&V40 G1–G10 PASS v2.1 cleanup queued

Production-grade quantitative systems pharmacology model of olipudase alfa enzyme replacement therapy for non-CNS manifestations of acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type B). Built using the IQANOVA ATLAS AI-QSP Master Pipeline v2.0 (14 stages). Calibrated against four clinical sources and one regulatory product information label. Open-source under MIT/CC-BY-4.0 dual licence.

Species:11 Parameters:53 Events:27 References:39 Files:~70

## Context-of-Use (COU)

Population-level inference for three regulatory questions:

- Adult-to-paediatric dose-bridging for olipudase alfa
- Long-term efficacy projection beyond the 2-year ASCEND-OLE horizon
- Identification of an ADA-positive sub-population

Risk classification per ASME V&V40-2018 §6.4: HIGH (model influence Medium × consequence High).

## Architecture (six layers)

1. PK — three-compartment plasma → tissue → lysosome
2. ADA — anti-drug antibody titre + ASM-activity neutralisation
3. Substrate — lysosomal sphingomyelin Michaelis–Menten
4. Biomarkers — plasma LysoSM and ceramide
5. Tissue burden — spleen, liver, lung, with saturation maxima
6. Clinical observables — volume %, DLCO, platelet, height-Z (paed)

## Headline pooled effects (Bayesian meta-analysis)

Endpoint | Pooled μ | 94 % HDI | R̂
--- | --- | --- | ---
DLCO change | +27.5 pp | [+16.9, +39.6] | 1.000
Platelet | +23.7 % | [+12.0, +35.5] | 1.010
Plasma LysoSM | −74.4 % | [−94.0, −46.1] | 1.010
Plasma Ceramide | −42.2 % | [−63.4, −19.3] | 1.010

All endpoints: ESS_bulk_min > 400. Model predictions sit inside 94 % HDI on every endpoint.

## Combination optimisation (W104 outcomes)

Four regimens evaluated. Across all four regimens × two populations, W104 outcomes differ by ≤ 0.5 pp on every endpoint.

Regimen | Decision
--- | ---
R1 — Label (3 mg/kg q2w) | PREFERRED
R2 — Reduced (2 mg/kg q2w) | STANDARD
R3 — Escalated (3→4 mg/kg q2w) | CONDITIONAL
R4 — Label + ADA(+) sub-pop | CONDITIONAL

Key clinical finding: the model is operating at saturation at label dose. Doubling/halving moves W104 by ≤ 0.5 pp. Label dose is the minimum effective dose at the W104 horizon.

## Pipeline phases (R1–R14)

Phase
Description
Verdict
Files
R1
Context-of-Use & risk
PASS
stage01_cou/
R2
SBML v2.0 build
PASS
stage02_sbml/
R3
Hypothesis specification
PASS
stage03_hypotheses/
R4
Synthetic data + provenance
PASS
stage04_data/
R5
Calibration (96 % PASS)
PASS
stage05_calibration/
R6
V&V (20/21 = 95.2 %)
PASS
stage06_vv/
R7
Global sensitivity analysis
PASS
stage07_gsa/
R8
Identifiability (FIM + PL)
PASS-COND
stage08_identif/
R9
Bayesian meta-analysis
PASS
stage09_bayes/
R10
Combination optimisation
PASS
stage10_combo/
R11
Master figures (4 + 10 supp)
PASS
stage11_figures/
R12
Regulatory package (8 docs)
PASS
stage12_regulatory/
R13
CPT:PSP submission
PASS
stage13_paper/
R14
ATLAS web page (this page)
PASS
stage14_atlas/

## Downloads

## SBML model files

adult.xml (L3v2, 0 err) paediatric.xml (L3v2, 0 err) build_summary.json

## Manuscript & supplementary

Manuscript (PDF) Cover letter (PDF) Supplementary index (PDF)

## Regulatory artefacts

Parameter table (xlsx) Model equations (PDF) References (PDF) Bayesian report (PDF) Identifiability (PDF) Reg. report R1–R14 (PDF)

## Master figures (PNG, 300 DPI)

Fig 1 — Architecture Fig 2 — Calibration Fig 3 — Biomarkers Fig 4 — Combinations

## v2.1 cleanup queue

- Re-parameterise observable maps to drop inert kinetic-rate parameters (DLCO_kinetic_rate, platelet_kinetic_rate)
- Constrain kcat_ASM with literature prior (Quintern 1989, Schuchman 2009)
- Two-compartment plasma ceramide submodel for paediatric heterogeneity
- Hill-saturation kinetics for adult LysoSM W52 nadir overshoot
- Non-centred reparameterisation for hierarchical Bayesian (eliminate ~5 % divergences)
- Add W4/W12 partial-response anchors when published — break lung kinetic-rate × max-frac compensation

## Citation

Goryanin I, Goryanin I. (2026) Mechanistic AI-QSP modelling of olipudase alfa therapy in acid sphingomyelinase deficiency: adult-to-paediatric bridging and regulatory-grade credibility assessment. CPT: Pharmacometrics & Systems Pharmacology [submitted]. Model artefacts at https://iqanova.org/atlas/asmd-xenpozyme-v2.