INTRANASAL FORALUMAB INFORM-MS KOL WEBCAST - TIZIANA LIFE SCIENCES LTD

Explicit Guidance:

• Clinical Trial Timelines: Top-line data from the Phase 2 Alzheimer's trial expected in Q1 2027 (approx. 3–5 months from release); Phase 2 Multiple System Atrophy (MSA) data expected within 3–4 months; ALS MyMatch trial data expected to read out in 2027.
• Regulatory Milestones: Plan to hold an FDA End-of-Phase 2 meeting to finalize protocols for pivotal trials (Phase 2b/Phase 3).

Business-Segment Outlook:

• SPMS (Inform-MS): Management confirms the primary endpoint (reduction in microglial activation via TSPO PET) was met at the 50 mcg dose; intends to advance to a pivotal, "approvable" trial based on current data.
• Disease Expansion: Strategy to utilize intranasal feralumab for "non-active secondary progressive" MS, MSA, Alzheimer's, and ALS, citing common neuroinflammatory mechanisms across these conditions.
• Dosage Strategy: Identification of 50 mcg as the optimal "sweet spot" dose for immune modulation; 100 mcg dose deemed exploratory and potentially less effective for primary PET endpoints in small samples, though showing fatigue benefits.

Market and Competitive Outlook:

• Unmet Need: Targeting the "silent" non-active SPMS patient population (approx. 25% of those on current anti-B cell therapies like ocrelizumab continue to progress) where no FDA-approved therapies currently exist.
• Differentiation: First non-invasive anti-CD3 therapy; mechanism targets microglial-driven neuroinflammation behind the blood-brain barrier, a target not addressed by current anti-B cell (CD20) therapies.
• Combination Potential: Anticipated market positioning includes combination therapy with existing CD20 inhibitors (e.g., ocrelizumab) to target both inflammatory and progressive components of MS; planning combination trial in Saudi Arabia with KMARC.
• PIRA Addressal: Expectation that feralumab will address Progression-Independent of Relapse Activity (PIRA), which affects ~30% of patients over two years even on standard therapies.

Macro / Industry Outlook:

• Regulatory Path: Active engagement with the FDA to define clinical outcome measures (fatigue MFIS vs. EDSS stabilization) for pivotal trials, building on the precedent set by recent failures of other MS drugs (e.g., Sanofi's tolobrutinib).
• Scientific Validation: Leveraging Nobel Prize-winning research on regulatory T-cells (T-regs) and microglial activation to support the mechanism of action and clinical rationale.

Strategic Initiatives:

• Pipeline Acceleration: Rapid execution of Phase 2 readouts for Alzheimer's (Q1 2027) and MSA (next 3–4 months) to validate the "common neuroinflammation" hypothesis across multiple neurodegenerative disorders.
• Expansion Programs: Ongoing Expanded Access/Open Label Extension programs for SPMS patients currently in trials.
• Strategic Partnership: Initiation of a combination trial with ocrelizumab in Saudi Arabia to test safety and efficacy in CD20-refractory patients.
• Trial Design Pivot: Exploring the use of MFIS (fatigue) and EDSS stabilization as pivotal endpoints for future Phase 2b/3 trials, citing the "spectacular" results in the Expanded Access program where EDSS stabilized in all patients.

Risks and Headwinds to Outlook:

• Trial Scope Limitations: Phase 2 was not statistically powered for secondary endpoints (fatigue, EDSS) or for the 100 mcg PET arm (small sample size of 11 patients), limiting definitive conclusions on dose-response for the higher dose.
• Timeframe Constraints: Three-month study duration limits ability to detect changes in long-term disability measures (EDSS) compared to Expanded Access Program (6–12 month) data.
• Imaging Variability: TSPO PET imaging involves inherent noise and complexity; management notes that "noise" in high-dose data may be sample-size related rather than biological failure.
• Regulatory Uncertainty: Final selection of pivotal trial endpoints (fatigue vs. disability vs. progression) remains under discussion with the FDA pending the End-of-Phase 2 meeting.

Management Tone on the Future:

• Confidence: High; described results as "spectacular," "very exciting," and "replicating" open-label findings in a blinded setting.
• Strategic Pivot: Explicit intent to move to pivotal trials, asserting data supports an "approvable" pathway.
• Validation: Strong emphasis on the convergence of clinical data (fatigue), biomarker data (PET), and immunological data (T-reg induction) as proof of mechanism.
• Hedges: Caveated the 100 mcg PET results as exploratory and underpowered; noted that EDSS changes in a 3-month period are not expected, shifting focus to longer-term trials for disability metrics.

Miscellaneous:

• Washout Protocols: Standardized 6-month washout for anti-CD20 antibodies and 1–2 months for oral medications prior to dosing in the INFORM-MS trial, per FDA protocol.
• Pre-existing Therapies: Majority of trial patients were on prior disease-modifying therapies (e.g., ocrelizumab) with inadequate response.
• Immunological Correlation: Ongoing analysis planned to correlate specific brain sub-regions (e.g., substantia nigra, hippocampus) with fatigue metrics to improve PET/fatigue alignment in future studies.