p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

Late-onset Alzheimer disease (AD) is the leading cause of dementia and involves multiple dysregulated mechanisms leading to synaptic failure and neurodegeneration. While amyloid-β (Aβ) and tau are key therapeutic targets, single-pathway approaches may not address the breadth of AD pathophysiology. Targeting ‘deep biology’ nodes that regulate multiple cellular pathways may normalize diverse pathological processes. p75 neurotrophin receptor (p75NTR) is a promising deep biology target influencing synaptic fate and neuronal survival. In its nonliganded or proneurotrophin-bound state, p75NTR promotes degenerative signaling; with mature neurotrophins, it can act as a Trk co-receptor supporting survival and plasticity. p75NTR signaling overlaps with pathways implicated in AD, including synaptic function and resilience. This trial tested whether modulating p75NTR with LM11A-31 is safe and can slow biomarkers of AD progression in patients with mild to moderate AD.

Multiple preclinical and human observations support p75NTR as an AD-relevant target: p75NTR-mutant mice show resilience to Aβ-related degeneration; human genetic variants in proneurotrophins and p75NTR co-receptors (sortilin, SorCS2) are associated with AD risk; p75NTR and pro-NGF are elevated in AD brain and CSF; and p75NTR is highly expressed in cholinergic basal forebrain neurons and other early AD-vulnerable populations. LM11A-31, derived from NGF loop-1 features, acts as a p75NTR modulator/antagonist to pro-NGF-induced degeneration, crosses the blood–brain barrier, and was nontoxic in preclinical studies. In AD and tauopathy models, oral LM11A-31 reduced tau pathology and seeding, glial activation markers, synaptic loss, and improved memory performance. It did not change plaque burden or soluble brain Aβ in APP transgenic mice, but protected against oligomeric Aβ-induced neurite and synaptic degeneration. Prior phase 1/1b studies in healthy participants established safety and CSF pharmacokinetics. These findings motivated a first-in-disease human trial in AD.

Design: 26-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2a trial of LM11A-31 (LM11A-31-BHS) in mild to moderate AD across 21 sites in five European countries (Austria, Czech Republic, Germany, Spain, Sweden). Ethics approvals obtained; trial conducted under ICH-GCP and Declaration of Helsinki. Registration: EU 2015-005263-16; NCT03069014. Participants: 316 screened; 242 enrolled (safety); 241 randomized (ITT). Inclusion: age 50–85 (50–80 in Czech Republic), AD by McKhann criteria, supportive MRI/CT, CSF Aβ42 < 550 ng/l or Aβ42/Aβ40 < 0.89, MMSE 18–26, low depression, adequate education/caregiver support/stable health and medications, stable AChEI/NMDA antagonist use ≥3 months. Exclusions detailed for comorbid neurologic/systemic conditions and prohibited medications. First 13 participants recruited under an earlier CSF criterion also satisfied revised criterion. Randomization and blinding: 1:1:1 to placebo, 200 mg, or 400 mg twice daily; stratified by site; identical capsules; sponsor, sites, participants, and caregivers blinded. Intervention: Self-administered oral capsules twice daily: placebo, 200 mg LM11A-31, or 400 mg LM11A-31. Sample size: Initially powered for effect size 0.56 with 51/group (80% power, alpha 0.05, two-tailed); increased to 80/group after blinded NTB variability review; capped by drug supply at 240 planned, 242 treated. Outcomes: Primary—safety and tolerability (AEs/SAEs, vitals, ECG, labs, MRI, suicidality scale). Secondary—CSF Aβ40, Aβ42, p-tau181, t-tau, CSF AChE; cognition via NTB composite. Prespecified exploratory—CSF synaptic markers (SNAP25, SYT1, NG), glial markers (YKL40, sTREM2), NfL; imaging (sMRI gray matter volume, [18F]-FDG PET metabolism); clinical: MMSE, ADAS-Cog-13, Amunet spatial task, Clinical Global Impression (CGI). Collection schedules per Extended Data Table 2. Biomarker assays: Core CSF biomarkers by Lumipulse automated immunoassays; SNAP25 and SYT1 by IP–MS; NG by in-house ELISA; sTREM2 by in-house MSD immunoassay; YKL40 by commercial ELISA; NfL by in-house ELISA; AChE activity by Ellman assay. Baseline and end-of-study samples run side-by-side; blinded to clinical data. Imaging: T1-weighted 3D sMRI and [18F]-FDG PET at baseline and end-of-treatment; preprocessing in SPM12/CAT12; longitudinal registration; PET SUVr normalized to AD-spared ROI; analyses restricted to AD-vulnerable masks defined from an independent ADNI cohort meeting trial-like criteria. Statistics: Primary safety with two-tailed tests, alpha 0.05. Secondary/exploratory endpoints largely nonparametric (Kruskal–Wallis for dose comparisons; Wilcoxon rank-sum for pooled drug vs placebo), with bootstrap 95% CIs for median differences. CSF longitudinal changes quantified as annual percent change controlling for interval differences. Cognitive changes computed as raw change (final–initial). Outliers (>3 MAD) removed; significance not corrected for multiple comparisons due to exploratory design. Imaging voxel-wise flexible factorial ANOVA models (group × time) within AD-vulnerability masks; uncorrected thresholds reported; post hoc majority-count and Monte Carlo simulations assessed hypothesis-consistent vs inconsistent voxel ratios. Analyses performed in SAS, MATLAB, and R.

Participants and disposition: 242 enrolled (safety); 241 randomized (ITT). 221 completed per protocol; 211 completed 26-week visit. Baseline: groups balanced for age (median 72), sex, MMSE (median 22), CSF Aβ42, AChEI use; all participants white; slightly higher APOE4 carriers in 400 mg (P=0.09). Primary safety: Primary endpoint met. Most common AEs: nasopharyngitis, diarrhea, headache, eosinophilia. Nasopharyngitis and diarrhea were significantly more frequent in 400 mg vs placebo (OR 5.41, 95% CI 1.15–25.52; OR 12.22, 95% CI 1.54–97.00; P<0.05). Headache occurred in 12 participants (2 placebo, 5 at 200 mg, 5 at 400 mg). Eosinophilia occurred in 10 participants (5 in each active dose), asymptomatic; 3 permanently discontinued; values resolved within ~1 month when followed. No eosinophilia in placebo. Total SAEs: 15 across 15 participants (2 pre-dose). Post-dose SAEs: 4 placebo, 2 at 200 mg, 7 at 400 mg; one GI bleed after 16 days possibly related; full recovery. Discontinuations: 20 total (AEs n=12: 2 placebo, 2 at 200 mg, 8 at 400 mg; SAEs n=4: 1 placebo, 3 at 400 mg; withdrawal of consent n=4). One death in placebo (pancreatic adenocarcinoma). No concerning MRI findings (including ARIA). Vital signs, ECG, and labs without significant abnormalities. Diastolic BP change differed across groups (P=0.036): median +1 mmHg (placebo), 0 (200 mg), −2 (400 mg); 400 mg vs placebo P=0.010; not clinically significant. DSMB found no overall safety concerns. Secondary CSF biomarkers: LM11A-31 slowed longitudinal increases in CSF Aβ42 (Pranksum=0.037; median annual percent change difference −6.98%, 95% CI −14.22% to −1.45%) and Aβ40 (P=0.009; −8.96%, 95% CI −17.60% to −1.29%). Aβ42/Aβ40 ratio unchanged (P=0.952; −0.42%, 95% CI −2.90% to 2.49%). p-tau181 NS (P=0.201; −5.54%, 95% CI −12.60% to 1.17%). t-tau trended lower (P=0.068; −6.07%, 95% CI −17.45% to 2.71%). CSF AChE activity NS (P=0.295; −3.12%, 95% CI −10.52% to 3.30%). Exploratory CSF biomarkers: Synaptic markers—SNAP25 decreased (P=0.010; −19.20%, 95% CI −32.19% to −1.47%); NG decreased (P=0.009; −9.17%, 95% CI −16.32% to −2.35%); SYT1 NS (P=0.426; −7.76%, 95% CI −20.13% to 4.99%). Degenerative marker—NfL NS (P=0.315; 3.13%, 95% CI −8.64% to 16.31%). Glial markers—YKL40 decreased (P=0.040; −5.19%, 95% CI −14.80% to 2.49%); sTREM2 NS (P=0.172; −4.29%, 95% CI −13.12% to 3.15%). Cognition and clinical: No significant differences between pooled LM11A-31 and placebo on NTB z-score at 12 weeks (P=0.156) or 26 weeks (P=0.185; median difference −0.03, 95% CI −0.10 to 0.04), ADAS-Cog-13 at 12 weeks (P=0.422) or 26 weeks (P=0.789; median difference −1 at both timepoints), or MMSE at 26 weeks (P=0.492; median difference +1). Placebo group showed median 26-week MMSE decline of 2 points and ADAS-Cog-13 increase of 2 points. CGI distributions did not differ (12 weeks P=1.00; final P=0.836). Amunet spatial memory tasks showed no treatment effect (P>0.10 across domains). Imaging: Within AD-vulnerable masks, voxel-wise sMRI showed hypothesis-consistent group×time interactions (uncorrected P<0.001) indicating slower gray matter loss with LM11A-31, notably in frontal operculum and posterior parietal cortex. FDG-PET showed no voxels at P<0.001 but at P<0.05 indicated slower metabolic decline in entorhinal/temporal cortex, hippocampus, insula, and prefrontal regions. Majority-count analyses favored hypothesis-consistent voxels: sMRI 3.1-fold (P<0.05) and 25.5-fold (P<0.01); PET 76.91-fold (P<0.05) and 89.95-fold (P<0.01); Monte Carlo P<0.001 at each threshold.

This first-in-disease phase 2a trial of p75NTR modulation with LM11A-31 in mild to moderate AD met its primary safety endpoint, supporting tolerability of 200 mg and 400 mg twice daily dosing. While cognitive outcomes were unchanged over 26 weeks—as expected for an exploratory, relatively short-duration and modestly powered study—the biomarker profile across CSF, sMRI, and FDG-PET was consistent with slowing of pathophysiological progression. LM11A-31 reduced longitudinal increases in CSF Aβ40 and Aβ42 without altering their ratio, suggesting effects on overall Aβ production or release rather than relative species distribution. It also decreased synaptic (SNAP25, NG) and glial (YKL40) biomarkers, aligning with preclinical evidence of enhanced synaptic resilience and reduced neuroinflammation via p75NTR modulation. Imaging results showed regions with slowed gray matter atrophy and glucose hypometabolism, reinforcing synaptic and neuronal support. The lack of cognitive benefit likely reflects trial duration and power constraints and does not preclude disease-modifying potential. Together, the data support engagement of p75NTR-influenced pathways relevant to synaptic integrity and glial activation and justify progression to larger, longer trials.

LM11A-31, a first-in-class modulator of p75NTR, was safe and well tolerated over 26 weeks in mild to moderate AD. Across prespecified exploratory biomarkers, LM11A-31 showed signals consistent with slowing of AD-related pathophysiology—lower CSF Aβ40 and Aβ42, reduced synaptic (SNAP25, NG) and glial (YKL40) markers, and attenuated sMRI and FDG-PET decline—without cognitive differences over 26 weeks. These findings support further development of LM11A-31 and the therapeutic strategy of targeting p75NTR. Future work should include larger, longer-duration, and more diverse cohorts; incorporate additional synaptic and glial markers; explore direct markers of p75NTR engagement; and investigate effects on APP processing/BACE1-related pathways.

- Short trial duration (26 weeks) and exploratory design limited power to detect clinical (cognitive) effects. - Multiple comparisons were not adjusted; several imaging findings reported at uncorrected thresholds. - Cohort comprised entirely white participants from European sites, limiting generalizability; need for diverse populations. - No direct in vivo biomarkers of p75NTR target engagement in humans. - Slight imbalance in APOE4 carrier frequency across groups (higher in 400 mg; P=0.09). - Higher discontinuations and some AE/SAE imbalances in the 400 mg group. - Imaging analyses constrained to AD-vulnerable masks and majority-count methods; confirmatory imaging endpoints needed in future trials.