📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

---

MAD Study Synopsis (TILA-278)

Document ID: CSR-102
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E3

Supporting Study — MAD Synopsis — TILA-278

Synopsis of the multiple-ascending-dose study of TILA-278: repeat-dose safety, PK accumulation, and early pharmacodynamics informing the Phase 2/3 regimen.

Name of Sponsor/Company	Virtual Biopharma Inc.
Name of Investigational Product	TILA-278 solution for subcutaneous injection
Name of Active Ingredient	TILA-278, a humanised bispecific IgG1 monoclonal antibody combining anti-TL1A (TNFSF15) antagonist activity with IL-22 receptor agonist activity, expressed in a Chinese hamster ovary (CHO) cell line
Title of Study	A Phase 1, Randomised, Double-Blind, Placebo-Controlled, Multiple-Ascending-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of Subcutaneous TILA-278 in Healthy Adult Participants (Protocol TILA278-102)
Protocol Number	TILA278-102
Development Phase	Phase 1
Studied Period	First participant enrolled: 14 March 2022. Last participant last visit: 27 January 2023.
Date of the Report	15 September 2023

Investigators and Study Centres

Single-protocol study conducted at two specialised clinical pharmacology (Phase 1) units with resident-stay capability and continuous cardiac and clinical monitoring. Central laboratory and central bioanalytical facilities supported all pharmacokinetic (PK), immunogenicity, and pharmacodynamic (PD) sample analyses. The Coordinating Investigator and the full list of investigators with their qualifications and unit identifiers are provided in Appendix 16.1.4. The study was conducted in accordance with ICH E6 Good Clinical Practice and under a United States Investigational New Drug application (21 CFR 312); TILA-278 is intended for future licensure under a Biologics License Application pursuant to 21 CFR 601.

Publication

None at the date of this report.

Objectives

Primary objective. To evaluate the safety and tolerability of repeat subcutaneous doses of TILA-278 compared with placebo in healthy adult participants.

Secondary objectives. To characterise the multiple-dose pharmacokinetics of TILA-278, including dose proportionality, accumulation, and the approach to steady state under a fixed-interval regimen; and to assess the immunogenicity of TILA-278 (anti-drug antibodies [ADA] and neutralising antibodies [NAb]).

Exploratory objectives. To describe the pharmacodynamic effects of TILA-278 relevant to each arm of the bispecific, including free and total TL1A (target engagement of the antagonist arm) and IL-22-pathway pharmacodynamic biomarkers (engagement of the agonist arm), and to explore PK/PD relationships to inform dose selection for later-phase studies.

Methodology

This was a Phase 1, randomised, double-blind, placebo-controlled, sequential multiple-ascending-dose study in healthy adult participants. Four ascending subcutaneous (SC) dose cohorts were studied. Within each cohort, participants were randomised 3:1 to TILA-278 or matching placebo. Each cohort received three SC doses administered at 2-week intervals (Days 1, 15, and 29), with a post-treatment follow-up period through Day 85 to characterise terminal elimination consistent with the extended half-life expected for an IgG1 antibody and to complete immunogenicity assessment.

Escalation to each successive cohort proceeded only after review of cumulative blinded safety, tolerability, and available PK data by a Safety Review Committee. Sentinel dosing was applied within each cohort (an initial sentinel pair, one active and one placebo, dosed and observed before the remainder of the cohort). Blinding was maintained by identical presentation of TILA-278 and placebo, dose-volume masking, administration by unblinded site staff not otherwise involved in assessments, and an interactive response technology system for allocation.

The pharmacological rationale reflects the dual mechanism of TILA-278: antagonism of TL1A (TNFSF15) attenuates TH1/TH17-driven inflammation and profibrotic signalling, while agonism at the IL-22 receptor promotes epithelial regeneration and mucosal-barrier repair. Because the molecule incorporates an agonist arm, the first-in-human and repeat-dose starting doses and escalation increments were established using a minimum anticipated biological effect level (MABEL) approach, integrated with the no-observed-adverse-effect level from repeat-dose toxicology in the cynomolgus monkey — the sole pharmacologically relevant toxicology species for TILA-278 — in accordance with ICH S6(R1). Consistent with regulatory expectations for a monoclonal antibody, and as reflected in the nonclinical programme, genotoxicity, carcinogenicity, hERG ion-channel, and dedicated thorough QT/QTc assessments were not warranted for this modality (ICH S6(R1); ICH S7B/E14 not applicable to a large-molecule antibody); routine 12-lead electrocardiographic (ECG) safety monitoring was nonetheless performed throughout.

Number of Subjects (Planned and Analysed)

Planned: approximately 32 participants (4 cohorts of 8; 6 TILA-278 and 2 placebo per cohort).

Randomised/Enrolled: 32 (TILA-278 24; Placebo 8).

Safety Analysis Set: all participants who received at least one dose of study drug — TILA-278 24; Placebo 8.

PK Analysis Set: all TILA-278 recipients with adequate concentration data — 24.

Immunogenicity Analysis Set: all TILA-278 recipients with at least one post-baseline ADA result — 24.

Sample size was based on the practical requirements of a Phase 1 safety, tolerability, and PK characterisation and was not derived from formal hypothesis-testing considerations.

Diagnosis and Main Criteria for Inclusion

Healthy adults aged 18 to 55 years with body mass index within the protocol-defined range, judged healthy on the basis of medical history, physical examination, vital signs, ECG, and clinical laboratory testing. Given the immunomodulatory mechanism, eligibility required negative screening for active or latent tuberculosis and for hepatitis B, hepatitis C, and HIV. Key exclusion criteria included clinically significant acute or chronic infection, recent or planned live-attenuated vaccination, use of immunosuppressive or immunomodulatory therapy, prior exposure to a biologic targeting TL1A or the IL-22 pathway, and any condition that in the investigator's judgment could confound assessment or compromise participant safety.

Investigational Product, Dose, Mode of Administration, and Batch Numbers

TILA-278 was supplied as a sterile solution for subcutaneous injection. The four ascending dose levels were 75 mg, 150 mg, 300 mg, and 600 mg administered SC at each dosing occasion; the required dose was delivered as one or more SC injections, with placebo injections added as needed to preserve equivalent injection number and volume across active and placebo assignments. Drug substance was manufactured by CHO cell culture with downstream purification incorporating Protein A affinity capture followed by polishing chromatography steps; specifications, comparability, viral safety, and stability were established in accordance with ICH Q6B, ICH Q5A(R2), and ICH Q5C. Investigational product batches: TL278-DP-2205 and TL278-DP-2210. Batch-to-participant allocation is provided in Appendix 16.1.6.

Duration of Treatment

Three SC doses administered at 2-week intervals (Days 1, 15, and 29), followed by a post-treatment observation period through Day 85.

Reference Therapy, Dose, and Mode of Administration

Matching placebo (identical solution presentation without active ingredient) administered subcutaneously on the same schedule as active treatment. Placebo batch: PLA-278-2204.

Criteria for Evaluation

Safety. Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, AEs leading to discontinuation, injection-site reactions, dose-limiting events, clinical laboratory parameters, vital signs, and 12-lead ECGs. Adverse events were coded using MedDRA and graded for severity and investigator-assessed relationship to study drug. Hypersensitivity and infusion/injection-associated reactions were monitored per protocol.

Pharmacokinetics. Serum TILA-278 concentrations were measured with a validated immunoassay specific for the intact bispecific antibody. Non-compartmental PK parameters included maximum observed concentration (Cmax), time to Cmax (tmax), area under the concentration–time curve over the dosing interval (AUC0–tau), terminal half-life (t½), and the accumulation ratio between the first and third doses. Dose proportionality was evaluated across the 75–600 mg range.

Immunogenicity. ADA were assessed using a validated, tiered assay (screening, confirmatory, and titre) with a validated cell-based NAb assay for confirmed-positive samples, with pre-specified evaluation of any impact on PK and safety.

Pharmacodynamics (exploratory). Serum free TL1A and total TL1A (reflecting antagonist-arm target engagement and drug–target complex accumulation) and IL-22-pathway pharmacodynamic biomarkers (reflecting agonist-arm engagement) were measured longitudinally over the dosing and follow-up periods.

Statistical Methods

Analyses were descriptive; no formal hypothesis testing was pre-specified. Safety, PK, immunogenicity, and PD data were summarised by cohort and by pooled treatment (TILA-278 versus placebo) using appropriate summary statistics. PK parameters were derived by non-compartmental analysis and summarised as geometric means with associated variability; dose proportionality was explored using a power-model regression of log-transformed exposure on log dose. The nonlinear disposition anticipated for an antibody subject to target-mediated drug disposition (TMDD) was considered in the interpretation of exposure across dose levels. Immunogenicity results were tabulated as incidence of treatment-emergent ADA and NAb, with exploratory assessment of exposure and safety in ADA-positive participants.

Summary of Results

Disposition

All 32 randomised participants (TILA-278 24; Placebo 8) received all three scheduled SC doses and completed the study; there were no discontinuations. Baseline demographic characteristics were comparable across cohorts and between pooled TILA-278 and placebo.

Safety

Repeat subcutaneous dosing of TILA-278 was well tolerated across all four dose cohorts. The maximum planned dose (600 mg) was reached, and no maximum tolerated dose was identified. There were no deaths, no SAEs, no severe TEAEs, and no AEs leading to discontinuation or dose interruption. TEAEs were predominantly mild and transient, with no dose-dependent trend in overall incidence. The most frequently reported events were injection-site reactions, headache, and nasopharyngitis; injection-site reactions were more frequent with active drug than with placebo and were the principal drug-attributable finding, consistent with subcutaneous administration of a biologic. No hypersensitivity or cytokine-release–type reactions, no clinically meaningful trends in haematology, chemistry, coagulation, or urinalysis, and no clinically significant vital-sign or ECG changes (including no QTc signal) were observed. The absence of a QT signal is consistent with the low expectation of direct cardiac ion-channel effects for a monoclonal antibody, for which hERG and dedicated thorough QT/QTc evaluation were not warranted.

Table 1. Overview of Treatment-Emergent Adverse Events (Safety Analysis Set), n (%)

Category	TILA-278 (N=24)	Placebo (N=8)
≥1 treatment-emergent AE	15 (62.5)	5 (62.5)
Injection-site reaction	7 (29.2)	1 (12.5)
Headache	5 (20.8)	2 (25.0)
Nasopharyngitis	4 (16.7)	1 (12.5)
Serious AE	0 (0.0)	0 (0.0)
Severe TEAE	0 (0.0)	0 (0.0)
AE leading to discontinuation	0 (0.0)	0 (0.0)
Deaths	0 (0.0)	0 (0.0)

Pharmacokinetics

Following subcutaneous administration, TILA-278 was absorbed with a median tmax of approximately 6 to 7 days and exhibited an extended terminal half-life consistent with an IgG1 antibody. Systemic exposure (Cmax and AUC0–tau) increased in a greater-than-dose-proportional manner across the 75 to 600 mg range, and the apparent terminal half-life lengthened with increasing dose — a pattern consistent with saturable, target-mediated clearance (TMDD) as target binding capacity is progressively exceeded at higher doses. Under the 2-week dosing interval, modest accumulation was observed, with accumulation ratios by the third dose of approximately 1.5 to 2.3 increasing with dose, and concentrations approaching steady state by the third dose. Absolute bioavailability was not assessed in this study, which did not include an intravenous reference arm.

Table 2. Multiple-Dose Pharmacokinetic Parameters After the Third Subcutaneous Dose (PK Analysis Set; geometric means)

Dose (SC)	N	Cmax (µg/mL)	tmax (day, median)	AUC0–14d (µg·day/mL)	t½ (day)	Accumulation ratio
75 mg	6	6.8	6	68	15	1.5
150 mg	6	16.5	6	178	18	1.8
300 mg	6	38.2	6	452	22	2.1
600 mg	6	82.6	7	1030	25	2.3

Immunogenicity

Treatment-emergent ADA were detected in 3 of 24 TILA-278 recipients (12.5%), predominantly at low titre and transient in the majority; NAb were confirmed in 1 of 24 recipients (4.2%). No discernible impact of ADA on TILA-278 exposure or on the safety profile was identified over the study period. The immunogenicity assessment reflects the expectation, standard for a therapeutic monoclonal antibody, that anti-drug antibody responses are a relevant characteristic to be monitored and interpreted in the context of PK and safety.

Pharmacodynamics (exploratory)

Dose-dependent engagement of both arms of the bispecific was demonstrated. For the antagonist arm, serum free TL1A decreased in a dose-dependent manner, with sustained suppression below the assay lower limit of quantification throughout the dosing interval by the third dose at the 300 mg and 600 mg levels, accompanied by a dose-dependent increase in total TL1A reflecting accumulation of drug–target complex — a pattern characteristic of a high-affinity antagonist antibody. For the agonist arm, IL-22-pathway pharmacodynamic biomarkers showed transient, dose-dependent increases that peaked within days of each dose and returned toward baseline before the subsequent dose, consistent with reversible IL-22 receptor agonism. Together these findings provided early confirmation that both the TL1A-antagonist and IL-22R-agonist activities of TILA-278 were pharmacologically active in vivo.

Conclusion

In this Phase 1, randomised, double-blind, placebo-controlled multiple-ascending-dose study in healthy adults, repeat subcutaneous TILA-278 was well tolerated at all four dose levels (75, 150, 300, and 600 mg), with no maximum tolerated dose identified, no SAEs or severe events, and no discontinuations; injection-site reactions were the principal drug-attributable finding and were predominantly mild and transient. The pharmacokinetics were consistent with an IgG1 antibody subject to target-mediated drug disposition, showing greater-than-dose-proportional exposure, a dose-dependent lengthening of terminal half-life, and modest accumulation under 2-week dosing. Immunogenicity was low and without apparent impact on exposure or safety, and exploratory pharmacodynamics confirmed dose-dependent engagement of both the TL1A-antagonist and IL-22R-agonist arms. The exposures achieved and the target-engagement profile at the 300 mg and 600 mg dose levels supported their selection, together with a repeat subcutaneous regimen, for evaluation as the Low and High induction doses in the Phase 2b study (TILA278-201) in moderately to severely active ulcerative colitis.

Date of the Report

15 September 2023.