Alector Pipeline Webinar: Advancing Next Generation Medicines for Neurodegeneration - ALECTOR INC

Explicit Guidance:

• AL-137 (Anti-A-beta Antibody):
  • Phase 1 (Healthy Volunteers): First-in-human dosing targeting April 2026 (Australia); IND filing to follow shortly; safety and exposure data expected by Q3 2027.
  • Phase 1b (Patients): To be conducted in the U.S. and Australia; enrollment planned for H2 2027 (approx. 15 patients plus 3-4 placebo controls across 3 doses); multiple monthly dosing regimen.
  • Efficacy Readouts: PET imaging and biomarker data accumulation expected from Q4 2027 through Q4 2028.
  • Clinical Targets: Aim to remove >90% of A-beta plaques within 3–6 months with monthly subcutaneous dosing; target reduction of >70% A-beta is considered the minimum threshold for clinical efficacy.
• AL-164 (Anti-Tau siRNA):
  • First-in-Human (FiH): Targeted initiation in Q2 2028.
  • Dosing Strategy: Subcutaneous delivery planned from start; aiming for one-month or greater maintenance dosing based on durability data showing >50% knockdown for >2 months in mice.
  • Knockdown Threshold: Targeting at least 50% MAPT mRNA knockdown in humans to balance efficacy and safety.
• AL-062 (Anti-alpha-Synuclein siRNA):
  • First-in-Human (FiH): Targeted initiation in Q2 2028 (parallel timeline with AL-164).
  • Dosing Strategy: Subcutaneous delivery; three-times-three mg/kg loading dose approach in preclinical studies achieved ~90% knockdown.
  • Knockdown Threshold: Targeting at least 50% alpha-synuclein reduction in humans, though aiming for higher levels (up to 90%) contingent on safety.
• Financial/Capacity:
  • Runway Extension: Partnership with Genentech/Roche extends corporate runway to 2029.
  • Pipeline Velocity: Goal to advance at least three programs (AL-137, AL-164, AL-062) to clinical stages using current resources.

Business-Segment Outlook:

• Portfolio Evolution: Transitioning from conventional antibodies to a platform driven by electro-brain carrier (EBC) technology, encompassing bispecific antibodies, enzymes, and nucleic acid therapies (siRNA).
• Target Validation: Shifting from "completely novel" targets to validated targets (A-beta, Tau, alpha-synuclein) to increase probability of technical success.
• Platform Flexibility: The EBC shuttle is described as "plug-and-play," allowing rapid deployment of different cargo molecules (antibodies, siRNA) to various targets without re-engineering the carrier.
• Manufacturing: Developing a productive process for low-cost goods of goods (COGS), particularly for subcutaneous delivery of AL-137; leveraging shared CMC processes for AL-164 and AL-062 due to identical ABC shuttles.

Market and Competitive Outlook:

• A-beta Landscape: Acknowledges a crowded field of 16+ antibodies; asserts only a small subset possess the triad of brain entry, validated epitope binding (pyroglutamate), and full effector function (immune cell recruitment).
• Competitive Differentiation: AL-137 aims to outperform Trantunumab (Roche) and Donanemab (Lilly) via superior brain exposure (predicted 2x exposure at half the dose), subcutaneous administration (vs. IV), and reduced anemia risk due to unique transferrin receptor epitope.
• Efficacy Thresholds: Management posits that <70% plaque removal yields no clinical benefit; competitors with reduced effector function (IgG2, IgG4) or modified epitopes are deemed high-risk for failure.
• Tau/Synuclein Landscape: Highlights failure of intrathecal ASO delivery (e.g., Biogen's Duranercin) due to heterogeneous brain distribution; positions peripheral siRNA conjugates (AL-164, AL-062) as superior for achieving homogeneous brain uptake.
• Market Size: Alzheimer's market projected at $70 billion with patient population expected to exceed 90 million by 2050.

Macro / Industry Outlook:

• Disease Trends: Recognition that while A-beta is a major cause, tau burden (not amyloid) is a stronger predictor of neurodegeneration speed and location; alpha-synuclein pathology is central to Parkinson's and Lewy Body Dementia.
• Regulatory Path: Planning to file INDs parallel to Phase 1 in healthy volunteers to facilitate rapid progression to patient studies in the U.S.
• Safety Standards: Management anticipates that transient, manageable anemia is acceptable (citing Roche's experience), but aims for a "clean" profile; no expectation of special delivery technology (e.g., infusions) required for AL-137 due to low-dose subcutaneous feasibility.

Strategic Initiatives:

• Genentech Partnership: Recent licensing agreement for the GKs enzyme (Parkinson's/Lewy Body Dementia) validates technology and funds clinical progression.
• Platform Expansion: Actively screening for additional siRNA targets beyond Tau and alpha-synuclein; maintaining capability for antibody and enzyme modalities based on target biology.
• Route of Administration: Strategic focus on subcutaneous delivery for all major programs to enable home administration, scalability, and reduced infusion reaction risks.
• Partnership Stance: Current intent is to advance AL-137, AL-164, and AL-062 internally using Genentech proceeds; will consider partnerships on an indication-specific basis (e.g., potential Parkinson's partnerships) but will not partner the core Alzheimer's/SYN programs at this time.

Risks and Headwinds to Outlook:

• Efficacy Risk: Modification of effector function (to reduce safety issues) is deemed a significant clinical efficacy risk due to unvalidated mechanisms; any drug failing to recruit microglia effectively is predicted to fail.
• Safety Risks: Potential for anemia (transferrin receptor binding on reticulocytes), ARIA (amyloid-related imaging abnormalities), and infusion reactions (though subcutaneous delivery is expected to mitigate these).
• Platform Optimization: Requires precise tuning of antibody affinity and epitope to balance brain uptake (TFR binding) with safety (avoiding reticulocyte damage); failure to optimize this "sweet spot" could compromise exposure or safety.
• Clinical Readout Uncertainty: Phase 1b efficacy data (PET, biomarkers) is not guaranteed; outcomes in early stages will determine continued investment in the programs.
• Target Uncertainty (Tau): Unknown "bell curve" for tau reduction; excessive knockdown could be detrimental, and ASO-based precedents showed confusion/inflammatory side effects (though siRNA is hoped to resolve this).

Management Tone on the Future:

• Confidence: High confidence in the reinvention of the company, citing the unique combination of validated epitopes, full effector function, and superior brain penetration as key differentiators.
• Aggressiveness: Management sets aggressive clinical goals (e.g., 90% plaque removal in 3-6 months) driven by the belief that current competitors lack sufficient potency or safety profiles.
• Reinforcement: Repeatedly emphasizes the de-risking of the A-beta program by leveraging clinical validation of the pyroglutamate epitope and IgG1 effector function from previous successful drugs.
• Strategic Clarity: Clear pivot to a multi-modality platform (antibody + siRNA) with the ambition to become the leader in brain-enabled delivery, supported by a solidified financial runway.

Miscellaneous:

• Data Readouts: Phase 1a safety data for AL-137 expected by Q3 2027; Phase 1b efficacy data accumulation spanning Q4 2027 to Q4 2028.
• Patient Selection: Early AD patients will be stratified by A-beta levels (PET) and MMSE, but not by tau levels, distinguishing from some competitor trials.
• Molecule Architecture: Preference for half-antibody format over FAB for siRNA conjugates due to superior half-life and avoidance of renal filtration, despite not requiring FC-mediated immune recruitment for siRNA.
• Cash Position: No immediate plans to terminate the ATM (At-The-Market) offering; cash position remains sufficient to support current internal development through 2029.