CHARDAN HEALTHCARE CONFERENCE – 10 YEARS OF DISRUPTIVE INNOVATION - SPERO THERAPEUTICS INC

Financial Performance:

• Secured $105 million in non-dilutive, non-recourse financing via partial monetization of commercial milestones from GSK license for the approved drug Dutepsi.
• Company operates with a cash runway extending into the second half of 2029.
• As a development-stage company, no current revenue from internal pipeline assets is reported.

Guidance and Future Outlook:

• Initiation of a Phase II trial for SP-001 in IgG4-related disease (IgG4RD) is guided for the second quarter of 2027.
• Phase II trial will utilize two dosing arms to gather data on efficacy and inform dose selection for future registrational trials.
• Partner InnoVent is guided to initiate a Phase II trial for SP-001 in Sjögren's syndrome by early 2027.
• Long-term goal is to establish the asset's role in addressing fibrosis and organ preservation beyond flare control.

Business Segments and Product Lines:

• Lead Asset (SP-001): A third-generation anti-CD40 ligand antibody with a fully silent Fc region designed to mitigate thrombosis risks associated with earlier generation CD40 antibodies.
• Therapeutic Focus: Repositioned around immunology, specifically targeting IgG4RD and Sjögren's syndrome to address fibrosis and tissue damage upstream of both T and B cells.
• Previous Asset: Commercial partner GSK to commercialize Dutepsi (the previously approved asset), providing the royalty stream for current financing.
• Strategic Shift: Focused exclusively on the SP-001 program following successful in-licensing due diligence (validating target, clinical data, IP, CMC, and regulatory interactions).

Market and Competitive Landscape:

• Differentiation: Unlike current competitors (e.g., Obilixamab, Oplezna) that primarily target B-cells for flare control, SP-001 targets CD40L upstream to modulate T-cells, B-cells, and antigen-presenting cells.
• Market Need: Addresses unmet needs in IgG4RD regarding long-term maintenance, prevention of organ damage, and fibrosis, areas where B-cell therapies may be insufficient.
• Competitive Landscape: First drug for IgG4RD was approved last year; other agents in development focus on B-cell inhibition, positioning SP-001 as a differentiated mechanism.

Risks and Challenges:

• Safety: Historical class effect of first-gen CD40 antibodies included thrombotic events due to Fc gamma R2A binding; SP-001 addresses this with a silent Fc region, validated in ~100+ human subjects with no observed thrombosis to date.
• Infection Risk: As an immunomodulator, monitoring for upper respiratory infections and general tolerability remains a critical safety focus.
• Delivery Modality: Current formulation is once-monthly IV, which may present a convenience hurdle compared to self-injected subcutaneous or oral alternatives, though IV is prioritized for initial Phase II proof of concept.

Management Commentary and Tone:

• Confidence: Management expressed high confidence in the safety profile (silent Fc) and the strategic rationale for targeting T-cells to address fibrosis.
• Rationale: Selected IgG4RD over Sjögren's as the primary Phase II indication due to the early lifecycle of the indication, high unmet need, and potential for a differentiated mechanism to cover disease aspects B-cell agents miss.
• Data Interpretation: Cautioned against direct cross-trial comparisons with Sjögren's Phase Ib data; viewed small dataset as contextual proof of activity across doses.

Analyst Questions and Answers:

• Question: Why prioritize IgG4RD over the larger Sjögren's market? Answer: IgG4RD is earlier in its lifecycle with an approved drug recently; CD40L's upstream mechanism may address fibrosis/organ damage better than B-cell agents, whereas Sjögren's data will evolve alongside IgG4RD progress.
• Question: How does SP-001 address the thrombosis risks of first-gen antibodies? Answer: SP-001 features a fully silent Fc region, which has been tested in ~100 humans (healthy volunteers and Sjögren's trial) without evidence of thrombotic events.
• Question: Where does SP-001 fit in the treatment paradigm relative to competitors like Obilixamab? Answer: It targets broader disease aspects (fibrosis, organ preservation) rather than just flare control; exact positioning (e.g., failure of B-cell therapy) is not yet defined as the disease understanding evolves.
• Question: What are the catalysts and runway? Answer: Catalyst is the Q2 2027 Phase II launch in IgG4RD; runway extends to H2 2029.

Other Key Points:

• Dosing Strategy: Phase II will test two doses to refine the dose-response curve for potential registration.
• Regulatory Approach: Management believes the existing data package from InnoVent positions the company well for FDA discussions regarding the Phase II design.
• Clinical Evidence: Mouse model data confirms biological activity but is not used for direct human dose translation; human PK/PD and safety data drive dosing decisions.