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Clinical Pharmacology — Human Pharmacokinetic Study Report (TILA-278)

Field	Value
Document ID	CLINPHARM-002
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH E3 / M4E
Confidentiality	Confidential

Clinical documentation for the TILA-278 program.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	Clinical	Initial issue

1. Synopsis

Sponsor: Virtual Biopharma Inc. Investigational product: TILA-278 — humanized IgG1 bispecific monoclonal antibody (anti-TL1A [TNFSF15] antagonist arm / IL-22 receptor agonist arm), sterile solution for subcutaneous (SC) injection. Protocol: TILA278-201 (Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction). Indication: Moderate-to-severe ulcerative colitis (UC). Report scope (CTD Module 5.3.3): Human pharmacokinetic (PK) study report describing SC absorption and bioavailability, distribution, target-mediated clearance, the population-PK (popPK) model, exposure by dose, and the effect of intrinsic and extrinsic covariates (body weight, serum albumin, anti-drug antibody [ADA] status, and baseline disease activity). Immunogenicity impact on PK and an integrated exposure-response summary are included. This report was authored in accordance with ICH E3 and ICH M4E.

Analysis populations. Of 1700 subjects screened, 900 were randomized 1:1:1 to TILA-278 High (n=299), TILA-278 Low (n=300), or placebo (n=301). The 599 active-arm subjects who received at least one dose and had at least one quantifiable post-dose serum concentration constituted the PK-evaluable population; 583 subjects contributing 4,921 quantifiable serum TILA-278 concentrations constituted the population-PK analysis set. A serial-sampling PK substudy enrolled 62 active-arm subjects.

Key PK findings (steady state, induction). TILA-278 exhibited PK typical of an IgG1 monoclonal antibody with target-mediated drug disposition (TMDD): slow SC absorption (median Tmax 6 days), a small volume of distribution approximating the vascular plus interstitial space (Vss~ ≈ 5.9 L), a long terminal half-life (t½ ≈ 19 days), and parallel linear plus saturable (nonlinear) elimination. Systemic exposure increased in a greater-than-dose-proportional manner between the Low (150 mg) and High (300 mg) regimens, consistent with saturation of the target-mediated clearance pathway at higher concentrations. Body weight and baseline serum albumin were the only covariates with a clinically meaningful effect on exposure; treatment-emergent ADA modestly increased clearance without a clinically relevant effect on the primary efficacy outcome at the doses studied. No covariate effect warranted dose adjustment.

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2. Introduction and Background

TILA-278 is a humanized IgG1 bispecific antibody engineered with one antigen-binding arm that neutralizes TL1A (TNFSF15) and a second arm that agonizes the IL-22 receptor (IL-22RA1/IL-10RB) complex. TL1A antagonism dampens TH1/TH17-driven inflammation and attenuates intestinal fibrosis, while IL-22R agonism promotes intestinal epithelial regeneration and mucosal-barrier repair. The two mechanisms are pharmacologically complementary — combining anti-inflammatory activity with mucosal healing — and are delivered from a single IgG1 scaffold retaining an intact Fc domain for neonatal Fc receptor (FcRn)-mediated recycling and an antibody-typical long systemic half-life.

Because both target epitopes are human-specific and the therapeutic is administered SC, the clinical pharmacology program was designed around the expectation of TMDD from both binding arms (a soluble and membrane-bound TL1A antagonist target and a membrane-bound IL-22R agonist target), incomplete but substantial SC bioavailability, and immunogenicity typical of a therapeutic antibody. This report characterizes the human PK of TILA-278 using intensive and sparse serum sampling from the pivotal induction study TILA278-201 and a population-PK analysis integrating those data.

Objectives of this report.

• Characterize SC absorption and estimate SC bioavailability.
• Characterize distribution and elimination, including the target-mediated (nonlinear) component of clearance.
• Describe the dose-exposure relationship across the Low and High regimens.
• Develop and qualify a population-PK model and quantify inter-individual variability.
• Quantify the effect of pre-specified covariates (body weight, serum albumin, ADA status, disease activity) on exposure and assess the need for dose adjustment.
• Summarize immunogenicity and its impact on PK, and integrate exposure-response for efficacy and safety.

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3. Bioanalytical Methods

3.1 Quantitation of TILA-278 in serum

Total serum TILA-278 was measured with a validated sandwich enzyme-linked immunosorbent assay (ELISA) using a recombinant capture reagent directed at the anti-TL1A arm and an anti-idiotype detection reagent directed at the IL-22R arm, providing selectivity for the intact bispecific molecule. Key validated performance characteristics were as follows:

Parameter	Value
Lower limit of quantitation (LLOQ)	0.100 µg/mL
Upper limit of quantitation (ULOQ)	30.0 µg/mL (higher concentrations by validated dilution)
Calibration range	0.100–30.0 µg/mL
Inter-assay accuracy (%bias)	−6.8% to +7.4%
Inter-assay precision (%CV)	≤ 11.2%
Selectivity / matrix effect	No significant interference from normal or UC serum

The method was validated in accordance with ICH M10. Concentrations below the LLOQ (BLQ) were handled in the population-PK analysis by the M3 likelihood-based method; in the non-compartmental (descriptive) analysis, leading BLQ values were set to zero and embedded/terminal BLQ values were treated as missing.

3.2 Immunogenicity assays

ADA were assessed using a tiered strategy: an electrochemiluminescence (ECL) bridging screening assay, a confirmatory assay with drug competition, and titer determination for confirmed-positive samples. Neutralizing antibodies (NAb) were evaluated with a competitive ligand-binding assay configured separately for each functional arm (inhibition of TL1A neutralization and inhibition of IL-22R engagement). Drug tolerance of the screening assay was ≥ 25 µg/mL at the low positive control. Assay cut points were established statistically per ICH-aligned immunogenicity guidance.

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4. Study Design and PK Sampling

4.1 Design overview

TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study in moderate-to-severe UC. Randomization (1:1:1) was stratified by baseline modified Mayo severity and prior biologic exposure. Study visits occurred at Weeks 0, 2, 4, 8, and 12; the primary efficacy endpoint was clinical remission (modified Mayo ≤ 2, no individual subscore > 1) at Week 12.

4.2 Dosing regimens

SC dosing was administered by prefilled syringe/autoinjector:

• TILA-278 High: 300 mg SC at Weeks 0, 2, 4, 8, and 12 (loading every 2 weeks through Week 4, then every 4 weeks).
• TILA-278 Low: 150 mg SC on the identical schedule.
• Placebo: matched SC injections on the identical schedule.

The Week 12 dose was administered after Week 12 efficacy and PK assessments.

4.3 PK and immunogenicity sampling

• Sparse (all active subjects): pre-dose (trough) serum at Weeks 0, 2, 4, 8, and 12.
• Intensive PK substudy (n=62 active subjects): serial serum sampling after the first dose (Day 1 [pre-dose and end of injection], Days 2, 4, 7, 10, and 14) and a full profile following the Week 8 dose, to characterize Cmax, Tmax, and the concentration-time profile.
• Immunogenicity: serum ADA at Weeks 0, 4, 8, and 12, and at early termination.

Actual sampling times were used for all PK computations.

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5. Absorption and Subcutaneous Bioavailability

Following SC administration, TILA-278 was absorbed slowly into the systemic circulation, consistent with lymphatic-mediated uptake of a large protein. In the intensive substudy, the median time to maximum concentration (Tmax) after the first dose was approximately 6 days (range 3–11 days), and the absorption profile was flat, producing modest peak-to-trough fluctuation at steady state — a desirable feature for a chronically dosed SC biologic.

First-dose non-compartmental parameters (geometric mean [geometric CV%]) were as follows:

Parameter	TILA-278 Low (150 mg)	TILA-278 High (300 mg)
Cmax (µg/mL)	10.4 (37%)	21.8 (34%)
Tmax (days), median (range)	6.5 (3–11)	6.0 (3–10)
AUC0–14d (µg·day/mL)	98 (41%)	215 (39%)

The population-PK first-order absorption rate constant (ka) was 0.264 day⁻¹, corresponding to an absorption half-life of approximately 2.6 days, with a short absorption lag (~0.15 day).

Because the study did not include an intravenous (IV) reference arm, absolute SC bioavailability was not directly estimable within TILA278-201. Absolute bioavailability was estimated at approximately 64% using a model-based approach anchored to the well-characterized disposition of intact human IgG1 (FcRn-recycled catabolism); this estimate should be interpreted with the caveat that it derives from a cross-referenced disposition assumption rather than an in-study IV comparison. The estimate is within the range expected for a full-length SC-administered monoclonal antibody.

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6. Distribution

TILA-278 displayed the limited tissue distribution characteristic of a monoclonal antibody. The estimated central volume of distribution (Vc) approximated plasma volume, and the total volume of distribution at steady state (Vss) was consistent with confinement to the vascular and interstitial compartments, with no evidence of extensive tissue partitioning or an active-transport distribution mechanism.

Distribution parameter	Population estimate
Central volume, Vc	3.18 L
Peripheral volume, Vp	2.71 L
Volume at steady state, Vss (Vc + Vp)	5.9 L
Intercompartmental clearance, Q	0.44 L/day

Distribution to the site of action (inflamed colonic mucosa) is inferred from the mechanism and from the pharmacodynamic response rather than measured directly. As with all IgG1 antibodies, transplacental transfer via FcRn increases across the second and third trimesters; this is addressed in Section 13.

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7. Elimination and Target-Mediated Drug Disposition

TILA-278 was eliminated by two parallel pathways, and the model that best described the data incorporated both:

1. Linear elimination reflecting nonspecific catabolism of IgG by the reticuloendothelial system and fluid-phase pinocytosis, partially opposed by FcRn-mediated recycling. This pathway dominates at the high concentrations achieved on-therapy.
2. Nonlinear, target-mediated elimination described by Michaelis-Menten kinetics (parameters Vmax and Km), arising from binding to and turnover of the drug-target complexes of both arms — soluble and membrane TL1A (which can act as a peripheral antigen sink) and cell-surface IL-22R (subject to receptor-mediated internalization). This pathway is quantitatively important at low concentrations (e.g., near trough and after the last dose) and becomes progressively saturated as concentration increases.

The interplay of these pathways produces the hallmark TMDD behavior of the molecule: apparent clearance decreases with increasing dose/concentration as target-mediated elimination saturates, and the terminal phase is governed by the slower linear pathway with FcRn support.

Elimination parameter	Population estimate
Linear clearance, CL	0.201 L/day
Maximum nonlinear elimination rate, Vmax	0.58 mg/day
Michaelis-Menten constant, Km	0.29 µg/mL
Terminal half-life, t½ (derived)	~19 days

Total apparent clearance at therapeutic steady-state concentrations approaches the linear value (~0.20 L/day) because the target-mediated component is largely saturated; at trough and during washout, effective clearance rises as target-mediated elimination re-engages.

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8. Dose-Exposure Relationship

Steady-state exposure was reached during induction with an accumulation ratio of approximately 1.8–2.2 relative to first dose, consistent with the ~19-day half-life and the loading-then-monthly schedule. Steady-state (Week 8–12) exposure parameters (geometric mean [geometric CV%]) were as follows:

Parameter	TILA-278 Low (150 mg)	TILA-278 High (300 mg)	High:Low ratio
Cmax,ss (µg/mL)	18.9 (42%)	47.5 (38%)	2.51
Ctrough,ss (µg/mL)	7.4 (54%)	21.6 (46%)	2.92
Cavg,ss (µg/mL)	13.2	34.3	2.60
AUCtau,ss (µg·day/mL)	370 (48%)	961 (41%)	2.60

For a 2-fold increase in dose (150 → 300 mg), AUCtau,ss increased approximately 2.6-fold and Ctrough,ss approximately 2.9-fold — a greater-than-dose-proportional increase in exposure. This is the expected consequence of TMDD: at the lower regimen a larger fraction of drug is eliminated by the saturable target-mediated pathway, so proportionally more is cleared, whereas at the higher regimen that pathway is more fully saturated and apparent clearance is lower. The disproportionate increase is most pronounced for trough concentrations, which sit lower on the concentration axis where target-mediated elimination contributes most.

Inter-individual variability in exposure was moderate (geometric CV% ~40–55%), typical for an SC therapeutic antibody in an inflammatory-bowel-disease population.

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9. Population Pharmacokinetic Analysis

9.1 Data and methods

The population-PK analysis included 583 subjects and 4,921 quantifiable serum concentrations from the sparse and intensive sampling schemes. Modeling was performed by nonlinear mixed-effects analysis (NONMEM v7.5, first-order conditional estimation with interaction [FOCE-I]). Model selection was guided by the objective function value, precision of parameter estimates, goodness-of-fit diagnostics, and physiological plausibility.

9.2 Structural and statistical model

The final model was a two-compartment model with first-order SC absorption (with lag) and parallel linear plus Michaelis-Menten (target-mediated) elimination. Inter-individual variability (IIV) was described with exponential random effects; residual variability used a combined proportional-plus-additive error model. Final parameter estimates were as follows:

Parameter	Estimate	RSE (%)	IIV (CV%)
ka (day⁻¹)	0.264	6.2	41.5
Absorption lag, ALAG (day)	0.15	12	—
SC bioavailability, F (relative)	0.64	5.1	27.8
CL (L/day)	0.201	3.8	31.2
Vc (L)	3.18	2.9	22.4
Q (L/day)	0.44	9.0	—
Vp (L)	2.71	6.1	28.0
Vmax (mg/day)	0.58	14.3	—
Km (µg/mL)	0.29	22.0	—
Proportional residual error (%)	17.8	7.4	—
Additive residual error (µg/mL)	0.08	19	—

9.3 Model qualification

The model was qualified by standard goodness-of-fit diagnostics (observed vs population- and individual-predicted concentrations, conditional weighted residuals versus time and versus prediction), a prediction-corrected visual predictive check (pcVPC) demonstrating that the 5th, 50th, and 95th percentiles of observed concentrations fell within the corresponding model-predicted intervals, and a nonparametric bootstrap (n=1000) in which median estimates and 95% confidence intervals were consistent with the final estimates. The model adequately described both the intensive first-dose profiles and the sparse trough data across the dose range.

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10. Covariate Effects

Pre-specified covariates were evaluated on clearance and central volume: body weight, baseline serum albumin, ADA status, baseline disease activity (baseline fecal calprotectin and baseline modified Mayo score), age, sex, and prior biologic exposure. Continuous covariates were modeled as power functions centered at the population median; ADA status entered as a categorical multiplier.

Covariates retained in the final model:

Covariate	Relationship	Point estimate
Body weight on CL	Power, centered 70 kg	Exponent 0.75
Body weight on Vc	Power, centered 70 kg	Exponent 1.0
Serum albumin on CL	Power, centered 40 g/L	Exponent −1.05
ADA-positive on CL	Categorical multiplier	1.28 (i.e., +28%)
Fecal calprotectin on CL	Power, centered 1200 µg/g	Exponent 0.06

Age, sex, and prior biologic exposure were not statistically significant after accounting for body weight and albumin and were not retained.

Impact on steady-state exposure (AUCtau,ss) across covariate ranges:

Covariate scenario	Effect on AUCtau,ss vs typical subject
Body weight 50 kg (vs 70 kg)	+38%
Body weight 110 kg (vs 70 kg)	−31%
Serum albumin 32 g/L (vs 40 g/L)	−18%
Serum albumin 46 g/L (vs 40 g/L)	+12%
ADA-positive	−22% (Ctrough,ss −35%)
Baseline fecal calprotectin at 95th percentile	−8%

Interpretation. Body weight and baseline serum albumin were the covariates with the largest influence on exposure. The albumin relationship (lower albumin → higher clearance → lower exposure) is well recognized for therapeutic antibodies in inflammatory bowel disease and reflects the shared catabolic/FcRn biology and protein loss associated with active mucosal inflammation; low albumin therefore behaves as a marker of disease burden as well as of enhanced antibody catabolism. Baseline fecal calprotectin (a direct disease-activity marker) had only a small independent effect once albumin was in the model, indicating that albumin captures most of the disease-activity signal on clearance. Despite these covariate effects, the range of resulting exposures remained within the range associated with near-maximal efficacy at the High regimen (Section 12); accordingly, no dose adjustment is recommended for body weight, albumin, disease activity, or ADA status at the doses studied.

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11. Immunogenicity and Impact on Pharmacokinetics

Treatment-emergent ADA were assessed using the tiered assay described in Section 3.2. Incidence and characteristics were as follows:

Immunogenicity endpoint	TILA-278 High	TILA-278 Low	Placebo
Treatment-emergent ADA, n (%)	28/298 (9.4%)	35/299 (11.7%)	6/300 (2.0%, background)
Persistent ADA, n (%)	11/298 (3.7%)	14/299 (4.7%)	—
NAb-positive (of ADA+), n (%)	10/28 (36%)	12/35 (34%)	—
Predominant titer category	Low	Low	—

Most ADA responses were low-titer and transient. ADA-positive subjects had approximately 28% higher clearance and correspondingly lower trough concentrations than ADA-negative subjects, quantitatively consistent with the covariate estimate in Section 10. This effect was largest, but still modest, in the small subset with persistent, neutralizing, higher-titer responses. Immunogenicity was not associated with a higher rate of injection-site reactions or hypersensitivity beyond the background rate, and — given the flat top of the exposure-response curve (Section 12) and the exposure margin at the High regimen — treatment-emergent ADA did not translate into a clinically relevant reduction in clinical remission at either active dose. ADA status is not a basis for dose adjustment at the doses studied.

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12. Exposure-Response (PK/PD) Summary

Efficacy. Clinical remission at Week 12 was dose- and exposure-ordered: TILA-278 High 37.3% (106/284), TILA-278 Low 16.2% (46/283), and placebo 0.7% (2/273). The LS-mean change from baseline in modified Mayo score at Week 12 was −3.36 (High), −2.76 (Low), and −1.00 (placebo); the differences versus placebo were −2.36 (95% CI −2.49, −2.23; p<0.0001) for High and −1.77 (95% CI −1.90, −1.64; p<0.0001) for Low. When remission was analyzed by steady-state trough (Ctrough,ss) quartiles pooled across active arms, the probability of remission rose with increasing exposure and began to plateau within the exposure range spanned by the High regimen, indicating that the High dose operates near the top of the exposure-response relationship while the Low dose sits on its ascending portion. This exposure-response behavior is coherent with the greater-than-dose-proportional PK (Section 8): a doubling of dose produces a >2-fold increase in exposure, translating into a substantial gain in remission from Low to High.

Safety. No exposure- or dose-dependence was observed for treatment-emergent adverse events. Across arms (High/Low/placebo), ≥1 TEAE occurred in 109/131/130 subjects, serious adverse events in 3/0/4, and deaths in 2/0/1 (all assessed as unrelated to study drug); discontinuations were 17/17/29 (the higher placebo rate driven by lack of efficacy). The most frequent adverse events were nasopharyngitis, headache, worsening UC (higher on placebo), anaemia, arthralgia, upper respiratory tract infection, injection-site reaction, and nausea. Injection-site reactions were the principal drug-attributable finding, occurred more often on active SC drug than placebo, and showed no relationship to systemic exposure. There was no dose-dependent safety signal, supporting a wide therapeutic margin over the induction exposure range.

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13. Special Populations and Intrinsic/Extrinsic Factors

• Body weight and albumin: the principal sources of PK variability (Section 10); neither warrants dose adjustment given the flat top of the exposure-response curve.
• Age and sex: no clinically relevant effect on exposure; not retained in the model.
• Renal and hepatic impairment: as a ~146-kDa monoclonal antibody, TILA-278 is not eliminated renally or by hepatic cytochrome-mediated metabolism; clinically meaningful effects of renal or hepatic impairment on PK are not expected, consistent with class understanding, and no dedicated organ-impairment study is proposed for this modality.
• Pregnancy/lactation: transplacental IgG1 transfer via FcRn increases in the second and third trimesters; exposure to the fetus later in pregnancy is anticipated for this class and is addressed in the risk-management framing of the program.
• Drug-drug interactions: direct pharmacokinetic interactions with small-molecule substrates are not anticipated for a monoclonal antibody. A theoretical cytokine-modulation ("therapeutic-protein DDI") effect on CYP-mediated metabolism cannot be excluded mechanistically; given the population and co-medication profile, no clinically significant interaction was identified.

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14. Cardiac Safety (QT) Waiver Rationale

TILA-278 is a large, target-specific monoclonal antibody with no expected off-target binding to cardiac ion channels (including hERG) and no small-molecule metabolites. Consistent with ICH E14/S7B Q&A principles for the QT/QTc evaluation of biologics, a dedicated thorough QT study is not warranted for this modality. No cardiac safety signal was observed in TILA278-201, and the nonclinical cynomolgus safety-pharmacology assessment did not identify cardiovascular liability.

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15. Conclusions

• TILA-278 exhibits pharmacokinetics characteristic of an IgG1 monoclonal antibody with target-mediated drug disposition: slow SC absorption (median Tmax 6 days), estimated SC bioavailability 64%, a small volume of distribution confined to the vascular/interstitial space (Vss ≈ 5.9 L), a long terminal half-life (~19 days), and parallel linear plus saturable elimination.
• Systemic exposure increases in a greater-than-dose-proportional manner from the Low (150 mg) to High (300 mg) regimen, reflecting saturation of target-mediated clearance at higher concentrations.
• A two-compartment population-PK model with first-order SC absorption and parallel linear + Michaelis-Menten elimination adequately described the data and was qualified by goodness-of-fit diagnostics, pcVPC, and bootstrap.
• Body weight and baseline serum albumin were the covariates with the greatest influence on exposure; disease activity acted largely through albumin. Treatment-emergent ADA (High 9.4%, Low 11.7%) increased clearance by ~28% but did not meaningfully reduce efficacy at the studied doses.
• Given the flat top of the exposure-response relationship at the High regimen, the absence of an exposure-dependent safety signal, and the modest, well-characterized covariate effects, no dose adjustment is recommended for body weight, serum albumin, disease activity, or ADA status. These PK, exposure, and covariate findings support the dose selection and dosing rationale carried forward for the program.

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16. Abbreviations

ADA, anti-drug antibody; AUCtau,ss, area under the concentration-time curve over the dosing interval at steady state; Cavg,ss, average steady-state concentration; Cmax, maximum concentration; Ctrough,ss, steady-state trough concentration; CHO, Chinese hamster ovary; CL, linear clearance; CTD, Common Technical Document; CV, coefficient of variation; ECL, electrochemiluminescence; ELISA, enzyme-linked immunosorbent assay; F, bioavailability; FAS, full analysis set; FcRn, neonatal Fc receptor; FOCE-I, first-order conditional estimation with interaction; IIV, inter-individual variability; IL-22R, interleukin-22 receptor; IV, intravenous; Km, Michaelis-Menten constant; ka, absorption rate constant; LLOQ, lower limit of quantitation; NAb, neutralizing antibody; NCA, non-compartmental analysis; pcVPC, prediction-corrected visual predictive check; PK, pharmacokinetics; popPK, population pharmacokinetics; Q, intercompartmental clearance; RSE, relative standard error; SC, subcutaneous; t½, terminal half-life; TL1A, TNF-like ligand 1A (TNFSF15); TMDD, target-mediated drug disposition; Tmax, time to maximum concentration; UC, ulcerative colitis; ULOQ, upper limit of quantitation; Vc, central volume of distribution; Vmax, maximum rate of nonlinear elimination; Vp, peripheral volume of distribution; Vss, volume of distribution at steady state.

Values marked represent standard, ICH-conformant clinical-pharmacology parameters consistent with a humanized IgG1 bispecific antibody exhibiting target-mediated disposition, where a specific value stands in for the corresponding measured result.