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DSMB Meeting Minutes (TILA278-201)

Document ID: TMF-007
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E6(R3)

DSMB Meeting Minutes — TILA278-201

These minutes constitute the cumulative record of the independent Data Safety Monitoring Board (DSMB) convened for Study TILA278-201, a Phase 2b, randomized, double-blind, placebo-controlled, 1:1:1 induction study of TILA-278 — a humanized IgG1 bispecific monoclonal antibody combining TL1A antagonism with IL-22R agonism, produced by CHO cell culture and administered subcutaneously — in adults with moderate-to-severe Ulcerative Colitis, sponsored by Virtual Biopharma Inc. The DSMB operated independently of the sponsor and of the investigators to safeguard participant welfare and the scientific integrity of the trial, reviewing accumulating unblinded safety data by treatment group, deliberating on the emerging benefit-risk profile, and issuing a documented recommendation to the sponsor (continue as planned / modify / suspend or stop) after each review. The Board's conduct, quorum, and documentation followed the pre-specified DSMB Charter, the sponsor's Safety Management Plan, applicable FDA guidance on the establishment and operation of clinical trial Data Monitoring Committees, and ICH E6(R3). FDA DMC guidance; ICH E6(R3).

1. Charter, Composition, and Independence

The DSMB Charter was executed and the Board constituted prior to first-participant-first-visit. The Charter defined the Board's authority, the statistical monitoring plan, stopping guidance, meeting cadence, unblinding procedures, and the firewall separating the DSMB from the sponsor's study team.

Voting membership was multidisciplinary and independent of the sponsor, the contract research organization, and all participating sites:

• Two board-certified gastroenterologists with inflammatory bowel disease expertise (one serving as Chair).
• One clinical immunologist, to advise on the immunomodulatory profile of a TL1A-antagonist / IL-22R-agonist bispecific and on immunogenicity findings.
• One hepatologist, given routine hepatic laboratory surveillance appropriate to a systemically administered biologic and the epithelial/acute-phase biology engaged by the IL-22R agonist arm.
• One independent biostatistician with data-monitoring experience.

Non-voting participants comprised the independent unblinded statistician from the Statistical Data Analysis Center (SDAC), who prepared closed-session reports directly from unblinded data, and — for open sessions only — a sponsor medical liaison who remained blinded to individual treatment assignment. Sponsor personnel involved in trial conduct had no access to unblinded, by-group data at any time. A quorum required the Chair (or designated Vice-Chair) plus a majority of voting members, including at least one clinician and the biostatistician. Conflict-of-interest declarations were collected at appointment and reaffirmed at each meeting; none rose to a level requiring recusal.

Each meeting followed a three-part structure: an open session (sponsor liaison present; enrollment, protocol conduct, and pooled/blinded data using neutral group codes A/B/C), a closed session (voting members and unblinded SDAC statistician only; fully unblinded data by actual treatment group — high-dose, low-dose, placebo), and an executive session (voting members only) at which the recommendation was finalized. Only the recommendation and non-confidential process notes were transmitted to the sponsor; unblinded results were withheld to preserve trial integrity.

2. Meetings Convened

Meeting	Type	Data reviewed	Format
DSMB-0	Organizational	Charter ratification, stopping guidance, table shells, dry-run report	Open + executive
DSMB-1	Periodic safety	First cohort through Week 4; cumulative safety by group	Open + closed + executive
DSMB-2	Periodic safety	Approximately full randomization; cumulative safety by group	Open + closed + executive
DSMB-3	End-of-induction safety	Complete randomized cohort through the Week 12 induction assessment	Open + closed + executive

The organizational meeting (DSMB-0) confirmed the Charter, reviewed the pre-specified safety events of special interest and the format of the closed-session reports, and rehearsed the reporting flow with dummy data. Subsequent meetings were triggered by enrollment milestones and by the calendar cadence defined in the Charter, with the Chair retaining authority to convene ad hoc reviews for any emergent safety concern. No ad hoc meetings were required.

3. Data Reviewed

Closed-session reports were provided by the SDAC as by-group summaries (high-dose, low-dose, placebo) with supporting participant-level listings. Cumulatively across screening and randomization, 1700 participants were screened and 900 were randomized 1:1:1 (299 high-dose, 300 low-dose, 301 placebo); the Full Analysis Set comprised 840 participants (284 high-dose, 283 low-dose, 273 placebo). At the end-of-induction review (DSMB-3), the Board evaluated the complete randomized population with subcutaneous study-drug exposure through the 12-week induction period. Enrollment pace, screen-failure reasons, and the balance of randomization across arms were reviewed and found consistent with the protocol.

The DSMB reviewed safety by treatment group across the following domains, with attention to the mechanism-informed events of special interest for this bispecific:

• Deaths and serious adverse events (SAEs) — cumulative incidence and narratives by group, with SAE relatedness as assessed by the investigators.
• Serious and opportunistic infections — a class-relevant focus given modulation of the TL1A (TNF-superfamily) axis; enteric, respiratory, and systemic infections were tabulated and reviewed for any dose-related trend.
• Hepatic events — transaminase and bilirubin elevations screened against Hy's-law criteria, reflecting routine biologic surveillance and the hepatic/acute-phase biology of IL-22R signaling.
• Hypersensitivity and injection-site reactions — systemic hypersensitivity events and local injection-site reactions consistent with subcutaneous administration, graded and tracked over repeated dosing.
• Immunogenicity — anti-drug antibody (ADA) and, where available, neutralizing-antibody incidence and titers, examined in relation to any loss of exposure (consistent with the target-mediated drug disposition, TMDD, behavior of the molecule) and to hypersensitivity or injection-site events.
• Epithelial and agonist-arm considerations — surveillance for any signal attributable to IL-22R agonism (e.g., epithelial proliferation, acute-phase/CRP shifts), reflecting the intended mucosal-healing mechanism.
• Malignancy — reviewed as a general consideration for immunomodulatory biologics.
• Laboratory and vital-sign trends — hematology (including neutrophils), chemistry, and lipids, plus routine electrocardiograms, reviewed by group.

The DSMB was reminded of the nonclinical context underpinning the monitoring plan: the cynomolgus monkey was the sole pharmacologically relevant species for the pivotal toxicology program (consistent with ICH S6(R1)), and, as expected for a monoclonal antibody, the program did not include genotoxicity, carcinogenicity, hERG, or thorough-QT assessments, none of which is warranted for this modality. The TMDD-driven, nonlinear pharmacokinetics informed the selected high- and low-dose subcutaneous regimens and the interpretation of exposure in the presence of ADA.

4. Benefit-Risk Discussion

At each review the Board weighed the accumulating safety experience against the mechanistic rationale and the emerging clinical benefit. TL1A antagonism was discussed as an anti-inflammatory and anti-fibrotic contribution, and IL-22R agonism as a driver of epithelial and mucosal healing; the combined mechanism framed the Board's interpretation of both safety and efficacy trends.

Across the domains above, the DSMB identified no unexpected safety signal and no dose-related imbalance that would alter the risk assessment. Deaths, serious infections, and hepatic events did not cluster in either active arm; no case met Hy's-law criteria for drug-induced liver injury. Injection-site reactions were predominantly low-grade and consistent with subcutaneous biologic administration. Immunogenicity findings were consistent with expectations for a humanized IgG1 and, on the data reviewed, were not associated with a discernible adverse safety impact or with an efficacy-relevant loss of exposure warranting action. Routine electrocardiograms were unremarkable, consistent with the absence of a cardiac-repolarization concern for a monoclonal antibody.

At the end-of-induction review, the Board considered topline efficacy provided by the SDAC to complete its benefit-risk assessment. Clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) at Week 12 was 37.3% (106/284) for high-dose, 16.2% (46/283) for low-dose, and 0.7% (2/273) for placebo. The key secondary endpoints were directionally concordant: the least-squares mean change from baseline in modified Mayo score was −3.36 (high-dose), −2.76 (low-dose), and −1.00 (placebo), corresponding to placebo-adjusted differences of −2.36 and −1.77; endoscopic improvement was observed in 48.9%, 27.9%, and 6.2% of the high-dose, low-dose, and placebo groups, respectively. The Board judged this dose-ordered efficacy, engaging both arms of the bispecific mechanism, to support a favorable benefit-risk balance in the studied population.

5. Recommendations

Following each closed and executive session, the DSMB communicated a written recommendation to the sponsor:

• DSMB-1: Continue the study without modification; no safety concern identified.
• DSMB-2: Continue the study without modification; the safety profile remained consistent across groups with no emergent signal.
• DSMB-3 (end-of-induction): No safety concern precluding completion of the induction analyses or continuation of the program; benefit-risk assessed as favorable, particularly for the high-dose regimen.

No recommendation to modify, suspend, or stop the study was issued at any meeting. The sponsor confirmed receipt of each recommendation and implemented no unblinding of its study team.

6. Attendance, Documentation, and Records

Attendance, quorum confirmation, and conflict-of-interest reaffirmations were recorded for each meeting. Draft minutes were prepared by the DSMB Chair (with SDAC support for the closed-session record), circulated to voting members for review, and finalized at or before the subsequent meeting. Open-session minutes are retained in the sponsor's Trial Master File; closed-session minutes and unblinded reports are retained separately under DSMB/SDAC control, without access by the sponsor's blinded study team, and are archived in accordance with the Charter and applicable retention requirements. These minutes are maintained as part of the essential document set supporting the marketing application and are available for inspection consistent with ICH E6(R3).