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SAD Study Synopsis (TILA-278)

Document ID: CSR-101
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E3

Supporting Study — First-in-Human SAD Synopsis — TILA-278

Synopsis of the single-ascending-dose study of TILA-278: safety, tolerability, and initial pharmacokinetics in healthy participants supporting dose escalation. ICH E3 (synopsis).

Name of Sponsor/Company	Virtual Biopharma Inc.
Name of Finished Product	TILA-278 solution for subcutaneous injection, 150 mg/mL
Name of Active Ingredient	TILA-278, a humanized IgG1 bispecific monoclonal antibody with an anti-TL1A (TNFSF15) antagonist arm and an IL-22 receptor (IL-22RA1/IL-10RB) agonist arm
Title of Study	A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Cohort, Single-Ascending-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Pharmacodynamics of TILA-278 in Healthy Adult Participants (Protocol TILA278-101)
Protocol Number	TILA278-101
Development Phase	Phase 1 (first-in-human)
Studied Period	First participant enrolled: 15 February 2022. Last participant last visit (end of follow-up): 03 November 2022.
Date of the Report	28 February 2023

This first-in-human study was conducted under a United States Investigational New Drug (IND) application (21 CFR Part 312) and supports the clinical development of TILA-278 toward a Biologics License Application (21 CFR Part 601). The nonclinical package enabling first-in-human dosing was designed in accordance with ICH S6(R1); the investigational drug substance and drug product used in the study were manufactured and controlled in accordance with ICH Q5A(R2) (viral safety), ICH Q5C (biotechnological product stability), and ICH Q6B (specifications for biotechnological products). This synopsis conforms to ICH E3.

Investigators and Study Centres

Single-centre study conducted at one qualified Phase 1 clinical pharmacology unit with dedicated inpatient monitoring, on-site resuscitation capability, and continuous medical cover appropriate for the first administration of a novel biologic to humans. The Principal Investigator, unit qualifications, and delegation log are provided in Appendix 16.1.4.

Publication

None at the date of this report.

Objectives

Primary objective. To evaluate the safety and tolerability of single ascending subcutaneous (SC) doses of TILA-278 compared with placebo in healthy adult participants.

Secondary objectives. To characterize the single-dose pharmacokinetics (PK) of TILA-278 following SC administration and to assess the immunogenicity (anti-drug antibodies [ADA]) of TILA-278 over the follow-up period.

Exploratory objectives. To assess pharmacodynamic (PD) evidence of target engagement of each functional arm of the bispecific molecule, including suppression of free (unbound) serum TL1A (antagonist arm) and modulation of IL-22 receptor–pathway biomarkers (agonist arm).

Methodology

This was a Phase 1, randomized, double-blind (participant- and investigator-blinded), placebo-controlled, sequential-cohort, single-ascending-dose study. Six sequential dose cohorts were enrolled. Within each cohort, participants were randomized in a 6:2 ratio to a single SC dose of TILA-278 or matching placebo, so that each cohort comprised 6 active and 2 placebo participants (8 participants per cohort).

To manage the risk associated with first administration of a bispecific antibody bearing a receptor-agonist arm, each cohort used sentinel dosing: on Day 1, one participant received active drug and one received placebo, and dosing of the remaining participants in that cohort proceeded only after a protocol-defined interval of at least 48 hours with satisfactory safety review. A Safety Review Committee (SRC) reviewed blinded and, when required, unblinded cumulative safety, tolerability, available PK, and PD data before authorizing each dose escalation. Escalation to the next dose level required acceptable safety and tolerability at the preceding level; predefined stopping and dose-adjustment rules governed the escalation.

The scientific rationale reflects the dual mechanism of TILA-278: antagonism of TL1A (TNFSF15) reduces TH1/TH17-driven inflammation and intestinal fibrosis, while agonism at the IL-22 receptor promotes epithelial regeneration and mucosal-barrier repair. The molecule is a full-length humanized IgG1 with an intact Fc domain, conferring neonatal Fc receptor (FcRn)-mediated recycling and an antibody-typical long systemic half-life. Because both target epitopes are human-specific and the drug is administered SC, the PK were expected to display target-mediated drug disposition (TMDD), incomplete SC bioavailability, and immunogenicity typical of a therapeutic antibody.

Selection of Starting Dose and Dose Range

The starting dose was selected using the minimum anticipated biological effect level (MABEL) approach in accordance with ICH S6(R1) and applicable first-in-human guidance for molecules with an agonist pharmacology. The MABEL was derived by integrating in-vitro potency and receptor-occupancy modelling for both functional arms, with the IL-22 receptor agonist arm governing the more conservative estimate, and was cross-checked against the no-observed-adverse-effect level (NOAEL) from the pivotal repeat-dose toxicology study. Consistent with the biology of both targets, the cynomolgus monkey was the sole pharmacologically relevant nonclinical species, and the toxicology and safety-pharmacology assessments supporting first-in-human dosing were conducted in that species; safety-pharmacology endpoints (cardiovascular, respiratory, and central nervous system) were incorporated into the repeat-dose study design as provided for under ICH S6(R1). Genotoxicity, carcinogenicity, dedicated safety-pharmacology core-battery (including hERG), and thorough-QT studies were not conducted, as they are not warranted for a monoclonal antibody of this class. The MABEL-based starting dose (5 mg SC) provided a substantial margin below the exposure associated with the NOAEL. The top planned dose (600 mg SC) provided coverage above the anticipated clinical exposure range while retaining an adequate safety margin.

Number of Subjects (Planned and Analysed)

Planned: 48 participants (six cohorts of 8; 36 active, 12 placebo).

Screened: 118. Randomized and dosed: 48 (TILA-278 36; placebo 12). Completed: 47. One participant (placebo) discontinued before the end of follow-up owing to withdrawal of consent for a reason unrelated to safety; no participant discontinued because of an adverse event.

• Safety Analysis Set (all participants who received study drug): 48 (TILA-278 36; placebo 12).
• PK Analysis Set (active participants with at least one quantifiable post-dose concentration): 36.
• Immunogenicity Analysis Set (participants with at least one post-dose ADA result): 48.

Table 1. Dose Cohorts (Sequential Ascending; Single SC Dose)

Cohort	Single SC dose	TILA-278 : placebo	N
1	5 mg	6:2	8
2	15 mg	6:2	8
3	50 mg	6:2	8
4	150 mg	6:2	8
5	300 mg	6:2	8
6	600 mg	6:2	8
Total			48

Diagnosis and Main Criteria for Inclusion

Healthy adults aged 18 to 55 years with a body mass index of 18.0 to 32.0 kg/m² and body weight ≥ 50 kg, judged healthy on the basis of medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory testing. Key exclusion criteria included clinically significant acute or chronic illness; evidence of active, chronic, latent, or recurrent infection (including screening for tuberculosis, hepatitis B, hepatitis C, and human immunodeficiency virus); recent or planned live-vaccine administration; prior exposure to any TL1A- or IL-22 pathway–directed agent; known hypersensitivity to a monoclonal antibody or excipient; and pregnancy or breastfeeding. Women of childbearing potential and men were required to use highly effective contraception per protocol.

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

TILA-278 drug substance is a humanized IgG1 bispecific monoclonal antibody produced by Chinese hamster ovary (CHO) cell culture and purified by a platform downstream process comprising Protein A affinity capture followed by orthogonal polishing chromatography and validated viral-clearance steps. The drug product is a sterile 150 mg/mL solution for SC injection.

Study drug was administered as a single SC injection into the abdomen by qualified unit staff. The 150, 300, and 600 mg dose levels were administered directly from the 150 mg/mL presentation (with the 600 mg dose divided across injections per the pharmacy manual to respect per-site volume limits); the 5, 15, and 50 mg dose levels were prepared by aseptic dilution of the 150 mg/mL drug product under the pharmacy manual to achieve a fixed injection volume. Identical injection appearance and volume were maintained between active and placebo assignments to preserve the blind. Drug product batch: TL278-DP-2108. Matching placebo batch: PLA-278-2106. Batch-to-participant allocation is provided in Appendix 16.1.6.

Duration of Treatment and Follow-up

Single dose on Day 1, followed by inpatient observation and a subsequent outpatient follow-up period extending to approximately Week 16 (Day 113) to characterize the terminal PK phase and washout given the anticipated long half-life, and to capture delayed immunogenicity. Safety, PK, and PD assessments were obtained at pre-dose and at scheduled times through the end of follow-up.

Reference Therapy, Dose, and Mode of Administration

Matching placebo (identical presentation, no active ingredient) administered as a single SC injection of identical appearance and volume to the corresponding active dose within each cohort. Placebo batch: PLA-278-2106.

Criteria for Evaluation

Safety. Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, adverse events leading to withdrawal, injection-site reactions, hypersensitivity and infusion/injection-related reactions, clinical laboratory parameters (haematology, chemistry, coagulation, urinalysis), vital signs, physical examination, and 12-lead ECG (including QTcF). Adverse events were coded using MedDRA and graded for severity and for relationship to study drug by the investigator. Dose-limiting events and protocol-defined stopping criteria were monitored by the SRC.

Pharmacokinetics. Serum TILA-278 concentrations were measured with a validated assay selective for the intact bispecific molecule. Non-compartmental parameters included maximum concentration (Cmax), time to Cmax (Tmax), area under the concentration–time curve to the last quantifiable concentration (AUC0–last) and, where estimable, to infinity (AUC0–inf), apparent terminal half-life (t½), and apparent clearance and volume terms. Dose proportionality across cohorts was assessed.

Immunogenicity. Serum ADA were assessed pre-dose and at scheduled post-dose visits using a validated tiered strategy (screening, confirmatory, and titre), with neutralizing-antibody characterization for confirmed-positive samples configured separately for each functional arm.

Pharmacodynamics (exploratory). Free (unbound) serum TL1A as a marker of antagonist-arm target engagement, and an IL-22 receptor–pathway biomarker panel (including serum REG3A and serum amyloid A) as a marker of agonist-arm engagement.

Statistical Methods

No formal hypothesis testing was planned; the study was descriptive and the sample size was based on convention for a first-in-human single-ascending-dose study rather than on statistical power. Safety data were summarized descriptively by dose cohort and for pooled placebo on the Safety Analysis Set. PK parameters were summarized by dose cohort using geometric means and geometric coefficients of variation (geometric CV%), with median and range for Tmax; dose proportionality was evaluated by a power-model analysis of dose-normalized exposure. Immunogenicity was summarized as the incidence and titre of treatment-emergent ADA. Exploratory PD endpoints were summarized descriptively over time by dose. Actual sampling times were used for all PK computations.

Summary of Results

Subject Disposition and Demographics

All 48 randomized participants received study drug and were included in the Safety Analysis Set (36 active, 12 placebo); 47 completed the study and 1 (placebo) withdrew consent for a reason unrelated to safety. The population comprised healthy adults aged 19 to 54 years with a body mass index of 18.5 to 31.8 kg/m², with both sexes represented; demographic and baseline characteristics were comparable across cohorts and between active and placebo assignments. Escalation proceeded through all six planned dose levels with SRC concurrence at each step.

Safety and Tolerability

Single SC doses of TILA-278 from 5 mg to 600 mg were well tolerated. No deaths, no SAEs, no severe TEAEs, and no adverse events leading to discontinuation occurred, and no dose-limiting toxicity was identified; the maximum tolerated dose was not reached within the planned dose range. No hypersensitivity, anaphylactic, or cytokine-release reactions were observed. TEAEs were predominantly mild (Grade 1) and transient and resolved without sequelae, with a similar overall incidence in the active and placebo groups. The most frequent events were headache, injection-site erythema/reaction, nasopharyngitis, and upper respiratory tract infection; injection-site reactions were the principal drug-attributable finding and occurred slightly more often with active drug than with placebo, consistent with SC administration of a biologic. There were no clinically significant dose-related trends in haematology, clinical chemistry, coagulation, urinalysis, vital signs, or 12-lead ECG parameters, including QTcF, and no dose-related ECG changes were observed.

Table 2. Overall Summary of Adverse Events (Safety Analysis Set), n (%)

Category	TILA-278 (N=36)	Placebo (N=12)
≥1 treatment-emergent AE	22 (61.1)	7 (58.3)
Drug-related TEAE	13 (36.1)	3 (25.0)
Severe TEAE	0 (0.0)	0 (0.0)
Serious AE	0 (0.0)	0 (0.0)
TEAE leading to discontinuation	0 (0.0)	0 (0.0)
Deaths	0 (0.0)	0 (0.0)

Table 3. Most Frequent Treatment-Emergent Adverse Events by Preferred Term (Safety Analysis Set), n (%)

Preferred term	TILA-278 (N=36)	Placebo (N=12)
Headache	6 (16.7)	2 (16.7)
Injection site erythema	5 (13.9)	1 (8.3)
Nasopharyngitis	4 (11.1)	1 (8.3)
Upper respiratory tract infection	3 (8.3)	1 (8.3)

Pharmacokinetics

TILA-278 exhibited PK characteristic of an IgG1 monoclonal antibody with target-mediated drug disposition. Following SC administration, absorption was slow, with a median Tmax of approximately 6 days across cohorts, consistent with lymphatic-mediated uptake of a large protein. Systemic exposure increased across the dose range in a greater-than-dose-proportional manner: dose-normalized Cmax and AUC rose with increasing dose, and the apparent terminal half-life lengthened toward the antibody-typical value (~19 days) at the higher doses. This behaviour reflects saturation of the target-mediated (nonlinear) elimination pathway at higher concentrations; at the lower dose levels a larger fraction of drug was cleared by the saturable target-mediated route, and the terminal phase could not be reliably characterized in the lowest cohorts because concentrations fell below the assay quantitation limit. These findings were consistent with the parallel linear (FcRn-supported catabolic) plus saturable Michaelis-Menten elimination model subsequently applied in the population-PK analysis of the program.

Table 4. Single-Dose Serum Pharmacokinetic Parameters, Selected Cohorts (PK Analysis Set; geometric mean [geometric CV%] unless noted)

Parameter	50 mg	150 mg	300 mg	600 mg
Cmax (µg/mL)	2.9 (39%)	10.4 (37%)	21.8 (34%)	46.2 (35%)
Tmax (days), median (range)	5.5 (3–8)	6.5 (3–11)	6.0 (3–10)	6.0 (4–10)
AUC0–14d (µg·day/mL)	26 (44%)	98 (41%)	215 (39%)	470 (37%)
Apparent terminal t½ (days)	~9	~13	~17	~19

Dose-normalized AUC0–14d increased monotonically with dose (0.52, 0.65, 0.72, and 0.78 µg·day/mL per mg at 50, 150, 300, and 600 mg, respectively), confirming greater-than-dose-proportional exposure across the studied range. The 5 mg and 15 mg cohorts showed measurable but low exposure with rapid decline consistent with dominant target-mediated clearance at low concentrations; robust non-compartmental parameters were not estimable at these levels.

Immunogenicity

Treatment-emergent ADA were infrequent. Across the active cohorts, treatment-emergent ADA were confirmed in 3 of 36 participants (8.3%); responses were low-titre and transient, with no confirmed high-titre or persistent neutralizing response. ADA status was not associated with any change in the safety profile and had no discernible effect on the single-dose PK at the sampled concentrations. The observed low-level, transient immunogenicity is consistent with expectations for a humanized IgG1 therapeutic antibody administered subcutaneously.

Pharmacodynamics (Exploratory Target Engagement)

Both functional arms of the bispecific engaged their targets in vivo. Free (unbound) serum TL1A declined in a dose-dependent manner following dosing; at the higher dose levels (≥ 150 mg) free TL1A fell below the assay quantitation limit and remained suppressed across the on-treatment sampling interval, recovering during washout in parallel with the decline in serum drug concentration — evidence of sustained antagonist-arm target engagement. Concurrently, the IL-22 receptor–pathway biomarker panel (including serum REG3A and serum amyloid A) showed transient, dose-dependent increases that peaked within the first week and returned to baseline as drug concentrations declined; these changes were asymptomatic, were not accompanied by clinical adverse events, and provided pharmacodynamic confirmation of agonist-arm engagement. Together these results demonstrated dual target engagement by the bispecific molecule after a single SC dose.

Conclusion

In this first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose study, single SC doses of TILA-278 from 5 mg to 600 mg were well tolerated in healthy adults. There were no deaths, SAEs, severe events, or dose-limiting toxicities, the maximum tolerated dose was not reached, and injection-site reactions were the principal drug-attributable finding. The PK were characteristic of an IgG1 monoclonal antibody with target-mediated drug disposition — slow SC absorption (median Tmax ~6 days), greater-than-dose-proportional exposure, and a terminal half-life approaching ~19 days at the higher doses. Immunogenicity was low-level and transient with no impact on safety or PK, and exploratory pharmacodynamics confirmed engagement of both the TL1A antagonist and IL-22 receptor agonist arms after a single dose. These results established an acceptable first-in-human safety, tolerability, and exposure profile and supported progression to multiple-ascending-dose evaluation and the selection of the SC dose range subsequently advanced into the induction study in ulcerative colitis.

Date of the Report

28 February 2023.

Abbreviations

ADA, anti-drug antibody; AUC, area under the concentration–time curve; Cmax, maximum concentration; CHO, Chinese hamster ovary; ECG, electrocardiogram; FcRn, neonatal Fc receptor; IgG1, immunoglobulin G subclass 1; IL-22R, interleukin-22 receptor; IND, Investigational New Drug application; MABEL, minimum anticipated biological effect level; MedDRA, Medical Dictionary for Regulatory Activities; NOAEL, no-observed-adverse-effect level; PD, pharmacodynamics; PK, pharmacokinetics; QTcF, Fridericia-corrected QT interval; SAE, serious adverse event; SC, subcutaneous; SRC, Safety Review Committee; t½, terminal half-life; TEAE, treatment-emergent adverse event; TL1A, TNF-like ligand 1A (TNFSF15); TMDD, target-mediated drug disposition; Tmax, time to maximum concentration; UC, ulcerative colitis.