Program Data Summary
Preclinical & clinical evidence supporting the Live-cel and T-rapa platforms across three lysosomal storage disorder programs
Contents
Program Pipeline Overview
| Program | Disease | Deficient Enzyme | Gene | Therapy Platform | Data Stage | Status |
|---|---|---|---|---|---|---|
| GT-GLA-S03 | Fabry Disease | Alpha-galactosidase A | GLA | Live-cel (Autologous LV-HSC) | Preclinical + Phase 1/2 PoC | Pre-IND |
| GT-GAA-S04 | Pompe Disease | Acid alpha-glucosidase | GAA | T-rapa Micropharmacy | Preclinical (In Vitro) | Pre-IND |
| GT-GBA1-S05 | Gaucher Disease | Beta-glucocerebrosidase | GBA1 | T-rapa Micropharmacy | Preclinical (In Vitro) | Pre-IND |
Fabry Disease: GT-GLA-S03 | Live-cel (Autologous LV-HSC Gene Therapy)
GT-GLA-S03 is an autologous lentiviral hematopoietic stem cell (HSC) gene therapy delivering a codon-optimized GLA transgene. Patient CD34+ cells are mobilized, transduced ex vivo with LV-AGA (self-inactivating lentiviral vector), and re-infused following non-myeloablative conditioning with melphalan 100 mg/mยฒ. Preclinical evidence was compiled for the GT-GLA-S03 INTERACT dossier; the FDA accepted Glafabra's INTERACT request as a face-to-face meeting on July 16, 2026, the highest-tier response available. Clinical proof of concept comes from the co-founders' FACTS trial.
G-CSF ยฑ plerixafor mobilization; CD34+ HSC collection (target 10 ×106/kg)
LV-AGA vector (SIN lentivirus); MOI 10; GMP-grade; VCN 0.68–1.43 copies/genome
Viability >70%; RCL negative; backup graft (2.5 ×106/kg unmanipulated) secured
Melphalan 100 mg/mยฒ IV; Day −1; non-myeloablative; outpatient feasible in 4/5 patients
Autologous transduced CD34+ cells; Day 0; 3.1–13.8 ×106 cells/kg infused
Neutrophil/platelet recovery Days 11–13; alpha-Gal A first detected Days 6–8; polyclonal reconstitution confirmed
| Model | Design | Key Findings |
|---|---|---|
| Vector Development & Iteration | Multiple recombinant LV vector architectures tested sequentially; promoter variants (EF1α, PGK, SFFV), codon-optimization, and WPRE inclusion compared for ฮฑ-gal A expression in Fabry patient CD34+ cells; LV/AGA (PGK + codon-optimized GLA + WPRE, SIN design) selected as optimal |
|
| Ex Vivo Transduction (Fabry Patient CD34+) | Fabry patient mobilized CD34+ hematopoietic cells transduced with near-clinical-grade LV/AGA at MOI 10; compared to mock-transduced Fabry CD34+ and to normal donor CD34+ cells |
|
| Fabry-to-Fabry BMT (Mouse) | LV/AGA-transduced vs. mock-transduced BM cells; endpoints at 3 and 6 months post-BMT; lethal irradiation conditioning |
|
| Xenograft (Human Fabry CD34+ in NSF Mice) | Near-clinical-grade LV/AGA; MOI 10; Fabry patient CD34+ cells; semi-lethal irradiation; endpoint 6 weeks |
|
| NSF Mouse Toxicology | LV/AGA vs. mock; Days 7 and 28 endpoints; CBC, blood chemistry, urinalysis, histology |
|
| NHP Safety Study (Same LV Backbone) | 3 male rhesus macaques; autologous mobilized PB cells; fully myeloablated; tracked >1 year (Walia et al. 2011) |
|
| NCT | NCT02800070 |
| Health Canada CTA | Approved April 26, 2016 |
| Phase | Phase 1 (Safety pilot) |
| Design | Multi-center, single-arm, open-label |
| Screened / Treated | 7 screened → 5 treated (2 failed screening) |
| Enrollment | September 2016 โ October 2018 |
| Follow-up | 5 years (End-of-Study February 2024) |
| Sites | Calgary AB · Toronto (UHN/Princess Margaret) · Halifax NS |
| Safety gating | Sequential enrolment; CTSC + DSMC review required before each successive patient authorized |
- Alpha-Gal A enzyme activity โ plasma, peripheral blood leukocytes, and bone marrow
- Lyso-Gb3 and Gb3 levels in plasma and urine
- VCN persistence in peripheral blood (qPCR)
- Anti-alpha-Gal A IgG antibody titres
5 Patients Treated โ Key Baseline & Product Characteristics
| Endpoint | Phase 1 Interim (18 months, 2021) | 5-Year End-of-Study (2025) |
|---|---|---|
| Plasma lyso-Gb3 | 40–86% reduction from baseline within 3 months; reduced in most patients | Significantly lower in 4/5 patients; stable from Years 1–5 |
| Alpha-Gal A activity | Detected Days 6–8 in all 5 patients; plasma reached reference range levels; leukocyte activity supranormal | Stabilized above Fabry disease baseline in all patients; not returned to pre-treatment levels; Patient 5 supranormal throughout |
| Vector copy number | Highest at 30–60 days; declining but durable (Patient 1: >0.05 copies/genome at ~3 years) | Polyclonal; no clonal dominance at 5 years; VCN mirrors enzyme activity (R² > 0.80) |
| Renal function (eGFR) | Stable in all patients; Patient 2 progressive CKD (pre-existing) | Patients 3–5 near 90 mL/min/1.73mยฒ; Patient 2 stabilized Year 3 (slope 0.11); Patient 1 slope 0.09 |
| Cardiac (LVMI) | Stable in all patients; no new LGE or T1 mapping changes | Patients 1, 2, 3 transient LVMI increase then reduction by Year 5; no LGE change in any patient |
| Product-attributable SAEs | 0 (5/5 patients) | 0 (5/5 patients, 5 years) |
| ERT discontinuation | 3/5 patients qualified and elected to stop ERT; Patient 3 never resumed | Estimated $4.8M CAD health system savings from ERT pause in 3 patients through last visit |
| Anti-alpha-Gal A antibodies | Pre-existing antibodies declined in 3/4 affected patients without resurgence | All antibody titres at or near baseline beyond 18 months; no sustained elevation in any patient at 5 years |
Data from the Canadian FACTs trial, reported across two publications: Khan et al. 2021 (PMC7907075) covering the first 2โ3 years of follow-up, and Khan et al. 2025 (PMC11726700) reporting the full 5-year end-of-study results.
Data sourcing methodology: Where available, early timepoint values (Year 0 through approximately Year 2โ2.7, depending on the biomarker) are taken directly from the machine-readable supplementary Excel tables published alongside Khan et al. 2021 โ these are exact measurements. For biomarkers where supplementary tabular data was not available (Leukocyte Alpha-Gal A, IgG Antibody Titre), or for the Year 2โ5 extension period covered only in the 2025 publication, values were digitized by visual inspection of the published figures in PMC11726700. Digitization precision varies by biomarker and y-axis scale: ยฑ0.3 nmol/min/mL for Plasma Alpha-Gal A (Fig. 2A), ยฑ0.3 nM for Lyso-Gb3 (Fig. 3B), ยฑ0.05 copies/genome for VCN (Fig. 4B), ยฑ2 mL/min/1.73mยฒ for eGFR (Fig. 4A), ยฑ10 nmol/hr/mg protein for Leukocyte Alpha-Gal A (Fig. 2B), and ยฑ15% on a log scale for IgG Antibody Titre (Fig. 5A). The IgG series additionally includes extrapolated Year 3โ5 values that extend each patient's established declining trajectory to background.
Each point represents a single measured value per patient. Year 0 = infusion date. Grey shaded bands indicate the published normal reference range for the relevant biomarker.
Fig. 1 โ Plasma Alpha-Gal A Activity Over Time (5-Year). All five patients began below the normal reference range (grey band, 5.1โ9.2 nmol/min/mL). Enzyme activity rose rapidly within weeks of infusion, reaching or exceeding the reference range in all patients by Month 3. Patient 5 (purple) remained at or above the upper reference range through Year 3.5. Patients 2โ4 stabilized in the 2.8โ4 nmol/min/mL range, detectably above the Fabry disease baseline, through Year 5. Patient 1 (teal) showed a gradual decline but remained above Fabry baseline at Year 5. Early timepoint data (Year 0โ2.7) from exact values in Khan et al. 2021 (PMC7907075); Year 3โ5 extension digitized from Khan et al. 2025 Fig 2A (PMC11726700).
Fig. 2 โ Leukocyte Alpha-Gal A Activity Over Time (5-Year). Leukocyte enzyme activity (nmol/hr/mg protein) provides a complementary engraftment readout to plasma activity. Grey dashed reference band marks the normal range (22โ57 nmol/hr/mg protein). Patient 5 (purple) showed a dramatically elevated early response โ peaking at ~330 nmol/hr/mg protein at Month 6 โ before declining to ~40โ60 nmol/hr/mg protein by Year 4โ5, near the upper reference range. Patients 1โ4 showed more modest early peaks with gradual plateau below the reference range, consistent with partial enzymatic correction. All data digitized from Khan et al. 2025 (PMC11726700, Fig. 2B, ยฑ10 nmol/hr/mg protein precision).
Fig. 3 โ Plasma Lyso-Gb3 Over Time (5-Year). Lyso-Gb3 (nM) is the primary pharmacodynamic endpoint planned for Glafabra's FDA trials โ more sensitive and disease-specific than total Gb3. The dashed grey line marks the published reference range upper limit (~3 nM). All patients reduced from pre-treatment baseline by Month 3. Patient 5 (purple) is the standout result: starting at 16.6 nM, lyso-Gb3 dropped below 10 nM by Year 0.5 and remained 5โ7 nM through all 5 years of follow-up โ approaching normal reference range and representing a 57โ68% sustained reduction. Patients 1 and 2 (teal, blue) stabilized in the 14โ19 nM range through Year 5 (>40% reduction from no-ERT baseline). Patient 3 (gold) reduced from a high baseline of ~70 nM at conditioning to ~30โ34 nM (Year 1โ5). Patient 4 (orange) showed ERT washout-driven early rise then stabilized around 35โ42 nM at Year 3โ5. Early timepoint data from exact values in Khan et al. 2021 (PMC7907075); Year 1.5โ5 extension digitized from Khan et al. 2025 Fig 3B (PMC11726700).
Fig. 4 โ Vector Copy Number (VCN) in Peripheral Blood Over Time. VCN (copies/genome) reflects durable engraftment of gene-corrected HSCs. Exact values from Year 0โ2 derive from supplementary data in Khan et al. 2021 (PMC7907075); Year 2โ5 extension digitized from Khan et al. 2025 (PMC11726700, Fig. 4B, ยฑ0.05 precision). All patients show a peak engraftment phase at ~1โ3 months post-infusion followed by stabilization at a durable plateau, consistent with polyclonal long-term repopulating HSCs. Patient 5 (purple) achieved the highest early and sustained VCN. VCN correlated strongly with plasma enzyme activity (R² > 0.80).
Fig. 5 โ eGFR Over Time (Years Post-Infusion). Early values (Year 0โ2.7) from exact supplementary data in Khan et al. 2021 (PMC7907075); Year 1.5โ5 extension digitized from Khan et al. 2025 (PMC11726700, Fig. 4A, ยฑ2 mL precision). Patients 3, 4, and 5 maintained eGFR above 110 mL/min/1.73m² through 5 years. Patient 1 (teal) oscillated around 75โ82 mL/min/1.73m², consistent with stable CKD Stage 2. Patient 2 (blue) enrolled with pre-existing Stage 3a CKD (eGFR ~50) and showed continued slow decline, with stabilization at ~25 mL/min/1.73m² from Year 3โ5. Horizontal dashed line marks the CKD Stage 3a/3b threshold (60 mL/min/1.73m²).
Fig. 6 โ IgG Antibody Titre Against AAV Vector Over Time. All values digitized from Khan et al. 2025 (PMC11726700, Fig. 5A, ยฑ15% precision on log scale). Y-axis is logarithmic to accommodate the full dynamic range. Patients 3 (gold) and 4 (red) mounted the highest early humoral responses, peaking at ~60,000 and ~30,000 respectively within 3โ6 months, then declining to baseline levels by Year 2โ3. Patient 1 (teal) showed a moderate early response (~10,000 peak) with gradual decline. Patient 2 (blue) remained near background throughout. Patient 5 (purple) maintained near-background IgG levels throughout follow-up, suggesting minimal humoral response to the AAV vector โ consistent with the superior sustained enzyme activity observed in this patient. Colored arrows in the source figure indicate ERT infusion timepoints per patient. The positive control (~640,000, not shown) and negative control were run alongside patient samples. Follow-up shown to Year 5; Year 3โ5 values for all patients extrapolated along their established declining trajectory (near baseline).
T-rapa Micropharmacy Platform Overview
The T-rapa Micropharmacy (TRaM) platform underpins GT-GAA-S04 (Pompe) and GT-GBA1-S05 (Gaucher). Rapamycin-conditioned CD4+ T cells are transduced with a lentiviral vector encoding the relevant lysosomal hydrolase. After re-infusion, engrafted TRaMs constitutively secrete functional enzyme into plasma and tissues, which is then taken up by enzyme-deficient bystander cells via the mannose-6-phosphate receptor pathway (cross-correction).
Autologous CD4+ T cells isolated directly from peripheral blood; no mobilization pretreatment required
1 µM rapamycin + CD3/CD28 beads + IL-2/IL-4 for 3 days; single LV transduction (MOI 30–60); Th2-polarized, central memory-enriched phenotype
Superior freeze-thaw survival vs. conventional T cells (P < 0.001); VCN confirmed; enzyme activity validated in vitro prior to release
Minimal pretreatment; no myeloablation required; supports outpatient administration and improved tolerability vs. HSC approaches
Autologous TRaMs infused; engraft systemically; constitutively secrete lysosomal enzyme into plasma and tissues
TRaMs distribute to liver, spleen, kidney, heart; long-term engraftment supported by rapamycin-induced central memory phenotype; re-administrable if needed
| Feature | Detail |
|---|---|
| Cell Source | Autologous peripheral blood CD4+ T cells; no pre-mobilization treatment required |
| Rapamycin Conditioning | 1 µM rapamycin for 3 days with CD3/CD28 beads (3:1), IL-2 (20 U/ml), IL-4 (1,000 U/ml); generates Th2-polarized, central memory-enriched phenotype; superior freeze-thaw survival vs. conventional T cells (P < 0.001) |
| Lentiviral Vector | SIN HIV-1-derived; EF1α promoter; WPRE element; MOI 30–60; titers 6–20 ×108 infectious particles/ml |
| Enzyme Secretion | 95–99% of enzyme activity in soluble fraction; 2–4% in extracellular vesicles (90–350 nm); appropriately glycosylated (pattern comparable to CHO-derived recombinant enzyme) |
| Uptake Pathway | Predominantly mannose-6-phosphate receptor (M6P); partially blocked by excess soluble M6P (>90% inhibition with HDo TRaM conditioned media); additional non-M6P pathways exist |
| Re-administrability | Autologous approach; no neutralizing antibody response; cells can be administered repeatedly |
| Clinical Context | Autologous Th1-polarized T-Rapa cells in active Phase II trial (NCT04176380); allogeneic Th2-skewed T-Rapa demonstrated successful engraftment with reduced-intensity conditioning (Fowler et al. 2013) |
Pompe Disease: GT-GAA-S04 | T-rapa Micropharmacy
GT-GAA-S04 applies the T-rapa platform to Pompe disease by encoding acid alpha-glucosidase (GAA) in the lentiviral transgene. Current data are in vitro, demonstrating successful transduction, supranormal intracellular GAA activity, and functional enzyme secretion from TRaMs. Source: Nagree et al., EMBO Mol Med 2022 (PMC8988206).
| Metric | Result |
|---|---|
| VCN Achieved (MOI 30–60) | 0.11–0.22 copies/genome across 3 healthy donors |
| Intracellular GAA Activity | Supranormal vs. non-transduced controls (P < 0.001); significant in both activated/dividing and quiescent states |
| Enzyme Secretion | Functional GAA secretion demonstrated; maintained in quiescent state at lower levels |
| Cytokine Production | Not suppressed by GAA transgene overexpression; normal T cell function preserved |
| T Cell Growth Response | Not suppressed in transduced cells; CD3/CD28 bead response intact |
| Cross-Correction Potential | Established in Fabry model (same platform); M6P receptor-mediated uptake by deficient bystander cells demonstrated |
Gaucher Disease: GT-GBA1-S05 | T-rapa Micropharmacy
GT-GBA1-S05 applies the T-rapa platform to Gaucher disease by encoding beta-glucocerebrosidase (GCase) in the lentiviral transgene. Current data are in vitro, demonstrating successful transduction, supranormal intracellular GCase activity, and functional enzyme secretion. Source: Nagree et al., EMBO Mol Med 2022 (PMC8988206).
| Metric | Result |
|---|---|
| VCN Achieved (MOI 30–60) | 0.21–0.33 copies/genome across 3 healthy donors (highest of the four TRaM constructs tested) |
| Intracellular GCase Activity | Supranormal vs. non-transduced controls (P < 0.001); significant in both activated/dividing and quiescent states |
| Enzyme Secretion | Functional GCase secretion demonstrated from transduced TRaMs |
| Cytokine Production | Not suppressed by GCase transgene overexpression; normal T cell function preserved |
| Asian Population Note | Gaucher disease carries elevated prevalence in Asian patient populations; relevant to Japan rights / co-development partnership strategy |
Platform Advantages
Non-Myeloablative Conditioning
Outpatient-feasible; lower toxicity burden
Melphalan 100 mg/mยฒ IV; single dose; administered Day -1 prior to infusion
4/5 FACTS trial patients received treatment as outpatients and returned home the same day; all 5 engrafted (Days 11–13)
Distinguishes Live-cel from AVROBIO's failed myeloablative approach; reduced cytopenia severity and improved patient experience
Re-Administrability
Structural advantage of the autologous approach
Autologous vector: no neutralizing antibody response to the gene therapy product itself; patient can receive a second dose if needed
Pre-existing anti-alpha-Gal A antibodies declined in 3/4 affected patients without resurgence; no sustained anti-enzyme antibody elevation at 5 years
Provides a path to re-dosing as HSC engraftment wanes over time; no competitive autologous program has demonstrated a neutralizing antibody concern
Shared Manufacturing
Three programs; one process
Fabry, Pompe, and Gaucher share a common manufacturing infrastructure; one IND enables learnings transferable across all three programs
Same LV backbone manufactured at Indiana University Vector Production Facility; all 5 patients treated from a single GMP lot in the FACTS trial
Miltenyi-instrumented CD34+ enrichment and transduction platform supports scalable, reproducible manufacturing; Orphan Drug Designation eligibility across all three diseases
- Non-myeloablative conditioning (100 mg/mยฒ melphalan); outpatient feasible
- Autologous: no neutralizing antibody response; re-administrable
- 5-year Phase 1/2 PoC with 0 product-attributable SAEs in 5 patients
- 40–86% lyso-Gb3 reduction within 3 months; durable suppression at Year 5
- Three-disease platform from one manufacturing process
- T-rapa isolatable from peripheral blood without pre-mobilization treatment
- FACTS trial enrolled only 5 male patients; larger trial needed
- Enzyme activity declined over time (VCN waning); long-term durability being assessed
- Pompe and Gaucher programs are in vitro only; no in vivo disease-specific data yet
- Company is pre-IND; FACTS PoC is co-founder work, not Glafabra's own IND-cleared program
- ERT withdrawal led to urine Gb3 increases in some patients (though eGFR remained stable)
Regulatory & Development Timeline
| Milestone | Date / Target | Status | Notes |
|---|---|---|---|
| FACTS Trial Completion (PoC) | 2016–2025 | Completed | 5-year end-of-study results published Jan 2025 (PMC11726700) |
| INTERACT Meeting (GT-GLA-S03) | July 16, 2026 | Confirmed | FDA accepted as face-to-face meeting (highest-tier response). FDA denies ~2/3 of INTERACT requests. Announced via press release May 9, 2026. |
| IND Filing (GT-GLA-S03) | Q1 2027 | Target | Proposed Phase 1/2, up to 10 patients, University of Utah Health (DCC and CelReGen). First Patient Enrolled target Q3 2027. |
| Orphan Drug Designation (ODD) | Granted / Pending | Granted (GT-GLA-S03) | ODD granted for Fabry (GT-GLA-S03); applications pending for Pompe (GT-GAA-S04) and Gaucher (GT-GBA1-S05). Confers 7 years U.S. market exclusivity upon approval. |
| Priority Review Vouchers (PRV) | TBD | Defensible (Pompe & Gaucher) | Pompe and Gaucher qualify for RPDD/PRV โ precedent established (Nexviazyme 2021, Pombiliti 2023), defensible value up to ~$200M. Fabry PRV is first-of-kind; treat as upside optionality. |