Slide 1: Interim Phase 1/2 Clinical Data of LX1001 for APOE4-associated Alzheimer's Disease
Interim Phase 1/2 Clinical Data of LX1001 for the Treatment of APOE4-associated Alzheimer’s Disease October 30, 2024 1 Exhibit 99.2
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, statements regarding Lexeo’s expectations and plans regarding its current product candidates and programs, including statements regardi
Slide 3: Advancing Genetic Medicines in Larger-Rare and Prevalent Patient Populations
Advancing Genetic Medicines in Larger-Rare and Prevalent Patient Populations Clinical: Discovery Preclinical Phase 1/2 Phase 2/3 Preclinical: Cardiovascular Indication: LX1001 LX1020 LX1021 Programs: Alzheimer’s: APOE4 homozygotes APOE4-Associated Alzheimer’s Disease FA(1) Cardiomyopathy PKP2-ACM(2)
Slide 4: APOE 4/4 Homozygotes: A Distinct, Genetically Defined Alzheimer's Disease Population
APOE 4/4 Homozygotes: A Distinct, Genetically Defined Alzheimer’s Disease Population APOE4/4 homozygotes exhibit earlier symptom onset, a distinct sequence of biomarker changes, and a faster rate of cognitive decline(3,4) ~2% of population Nearly all APOE4 homozygotes will develop Alzheimer’s sympto
Slide 5: APOE4 Is A Known Driver of Alzheimer's Risk, Affecting Multiple Pathways
APOE4 Is A Known Driver of Alzheimer’s Risk, Affecting Multiple Pathways Neuroinflammation Tau aggregation Mitochondrial dysfunctional Aß deposition/clearance Synaptic deficits Neurotoxicity APOE4 APOE4 drives Alzheimer’s disease pathogenesis Associated with toxicity to neurons Accelerates amyloid d
Slide 6: APOE2 is Protective Across Multiple Pathways; Increasing APOE2/4 Ratio Can Dilute APOE4
APOE2 is Protective Across Multiple Pathways; Increasing the Ratio of APOE2/4 Can Dilute APOE4 Toxicity and Express APOE2 Protectivity Martins, C.A.R. et al. APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology. 2005; 65(12):1888-93. doi: 10.1212/01.w
Slide 7: Unique Approach to Targeting Underlying Genetics of APOE4/E4 Alzheimer's Disease
Unique Approach to Targeting Underlying Genetics of APOE4/E4 Alzheimer’s Disease LX1001 Mechanism of Action: Gene therapy delivering protective APOE2 transgene to the CNS of APOE4 homozygotes Phase 1/2 First & only clinical-stage gene therapy candidate targeting genetics of APOE4/4 AD Differentiated
Slide 8: Phase 1/2 Trial in APOE4 Homozygotes
LX1001 Phase 1/2 Trial in APOE4 Homozygotes Key Inclusion Criteria: ≥50 yr APOE4 homozygotes Mild cognitive impairment (MCI) to moderate dementia with biomarkers (amyloid PET and CSF) consistent with Alzheimer’s disease Cohort 1 n=5 Cohort 2 n=4 Cohort 3 n=3 1.4x1010 vg/ml CSF 5.7x1012 Total VGs 4.4
Slide 9: At Baseline, Cohorts Include Patients with More Advanced Disease
At Baseline, Cohorts 1 and 3 Include Patients with More Advanced Disease Baseline Characteristics Cohort 1 (n=5*) Cohort 2 (n=4) Cohort 3 (n=3) Cohort 4 (n=3) Total (n=15) Demographics Age, years, mean (SD) 63.8 (5.5) 64.3 (2.2) 63.7 (12.2) 70.7 (3.5) 65.3 (6.4) Sex – Female, n (%) 5 (100) 4 (100) 2
Slide 10: Was Well Tolerated Across All Four Dose Cohorts
LX1001 Was Well Tolerated Across All Four Dose Cohorts Treatment with LX1001 was well-tolerated across all 4 dose cohorts No reports of ARIA(1) Transient CSF pleocytosis (>5cells/μL), predominantly lymphocytic, was observed in 12 participants, with no significant adverse events associated Four SAE’s
Slide 11: APOE2 Protein Expressed in CSF in All Participants
APOE2 Protein Expressed in CSF in All Participants, with Dose- and Time-Dependent Increase in Expression and Durability to 12 Months APOE2 (fmol/µl) – Mean APOE4 (fmol/µl) – Mean APOE 2:4 Ratio (%) – Mean Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 3 Outlier Cohort 3 Outlier Screening Day 1 Month 3 M
Slide 12: Stabilized Amyloid Progression in Majority of Participants at Last Follow-Up
LX1001 Stabilized Amyloid Progression in Majority of Participants at Last Follow-Up CSF Aß42/40 Amyloid PET – SUVR Majority of patients with minimal change from baseline Change from Baseline (Ratio) Mean Change from Baseline (SUVR) At 12 months or last follow up, patients remained similar to baselin
Slide 13: Reduced CSF T-Tau & P-Tau181 at Last Follow-Up
LX1001 Reduced CSF T-Tau & P-Tau181 in 9 of 13 Patients at Last Follow-Up CSF T-Tau CSF P-Tau181 Note: Assay variability within +/- 6% PBO = Placebo, LEC = Lecanemab. *Indicates results as of 6-month visit. Each bar represents absolute change from baseline per participant at 12 months, or last follo
Slide 14: Reduced P-Tau217 & P-Tau231 at Last Follow-Up
LX1001 Reduced P-Tau217 & P-Tau231 In 4 of 6 Patients at Last Follow-Up CSF P-Tau231 (12 month) Note: Assay variability within +/- 6% *Indicates results as of 6-month visit. Each bar represents absolute change from baseline per participant at 12 months, or last follow up if 12-month follow-up unavai
Slide 15: Reduced Tau Burden via Global SUVR (PET)
LX1001 Reduced Tau Burden via Global SUVR (PET); Highly Correlated Predictor of Cognitive Outcomes Driven by Alzheimer’s Disease(1) Tau PET – Global SUVR Note: APOE4/4 NHx progression represents natural history for tau PET in E4 homozygotes over 12 months per ADNI database, converted from centiloids
Slide 16: Reduced Tau Burden via Regional SUVR (PET)
LX1001 Reduced Tau Burden via Regional SUVR (PET), Indicating Reduction of Tau Propagation and Slowing of Disease Progression Tau PET – Regional SUVR 6-Month (n=6) Medial Temporal Temporal Parietal Cingulate Frontal Occipital 12-Month (n=2) Improvement Improvement C4 not yet available Cohort 3 outli
Slide 17: Phase 1/2 Key Takeaways
LX1001 Phase 1/2 Key Takeaways Confidential Safety Well-tolerated across all cohorts No reports of ARIA Four SAEs, one possibly treatment related Efficacy APOE2 expressed in CSF of all participants, with dose-and time-dependent increase in E2:E4 expression Stabilization of amyloid pathology Consiste
Slide 18: Regulatory Precedent for Biomarker-Based Approvals in Alzheimer's and Gene Therapy
Regulatory Precedent for Biomarker-Based Approvals in Alzheimer’s and Gene Therapy Accelerated approval based on reduction in amyloid plaques as seen in amyloid-PET scans Regulatory precedent: accelerated approval of two Alzheimer’s therapies to date Ioannou, K. et al. Tau PET positivity predicts cl
Slide 19: Encouraging Clinical Data with Potential Path to Accelerated Approval
LX1001 Offers Encouraging Clinical Data with Potential Path to Accelerated Approval Meaningful impact across hallmark Alzheimer’s biomarkers Consistent reduction in Tau biomarkers that are highly correlative to progression & cognition Patient population with worse prognosis and no suitable alternati
Slide 20: Q&A
Q&A 20