LM11A-31 drug slows progression of Alzheimer's disease in trial

In a recent study published in Nature Medicine, researchers conducted a randomized, double-blind, placebo-controlled Phase 2a trial to examine the safety and effectiveness of LM11A-31 in treatment of Alzheimer's disease (AD) through modulation of the p75 neurotrophin receptor (p75NTR).

Late-onset AD is the most common form of dementia, characterized by synaptic failure, degeneration and loss of nerve cells. Although the two main drugs for treating AD target the accumulation of abnormal amyloid-β or tau protein, they address only part of the pathophysiology. Another approach is to target receptors and signaling networks that influence fundamental biological pathways. Preclinical studies show that modulation of p75NTR with the novel small molecule LM11A-31 reduces synaptic loss caused by amyloid and pathological tau.

Description of the study

In this randomized clinical trial, researchers examined whether LM11A-31 could slow the progression of Alzheimer's disease by modulating p75NTR in humans.

Study participants were given oral capsules of LM11A-31 at doses of 200 mg and 400 mg or placebo in a 1:1:1 ratio to 242 patients with mild to moderate asthma for 26 weeks. Participants had biologically confirmed Alzheimer's disease (cerebrospinal fluid amyloid β protein 42 (Aβ42) level below 550 ng/L or Aβ42:β40 ratio below 0.89), diagnosed according to McKhann criteria, with Mini Psychiatric SE (MMSE) scores of 18 to 26, Geriatric Depression Scale (GDS) scores below 5.0, modified Hacinski Ischemic Scale (HIS) scores ≤ 4.0, formal education ≥ 8 years, and previous cognitive decline ≥ 6 months.

Eligible participants had been taking acetylcholinesterase inhibitors (AChEIs) or partial NMDA receptor antagonists ≥ 3 months before study entry. They were not taking illicit drugs such as antipsychotics, benzodiazepines, antiepileptic drugs, sedatives, centrally active antihypertensive drugs, nootropics (except ginkgo biloba) or analgesics containing opioids.

The primary outcome of the study was drug safety and tolerability as assessed by the Columbia Suicidal Ideation and Behavior Severity Rating Scale (C-SSRS), vital signs, blood pressure, and hematologic parameters. Structural magnetic resonance imaging (sMRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers were used to assess secondary cognitive outcomes. AD indicators included tau phosphorylated at Thr181, total tau protein, Aβ40, Aβ42, and AChE activity. The team used an individualized neuropsychological test to assess secondary cognitive outcomes at baseline, weeks 12, and 26.

Research results

The study found that LM11A-31 was safe and well tolerated, with no significant safety concerns. The most common side effects included headache, diarrhea, eosinophilia and nasopharyngitis, with gastrointestinal problems and eosinophilia being the main reasons for discontinuation of the drug. There were more discontinuations in the 400 mg group compared with the 200 mg and placebo groups. MRI revealed no drug safety concerns, including amyloid-related abnormalities. There were no significant differences in cognitive scores or amyloid abnormalities between the two treatment groups.

A. Two-factor mixed models analyzes of covariance examined interactions between treatment (drug or placebo) and time (pre- or post-treatment). A one-way t-contrast examining the interaction hypothesis (drug slows progression compared with placebo) showed that LM11A-31 treatment slowed longitudinal degeneration (left panels) and glucose hypometabolism (right panels) in the drug-treated group (cMRI, n = 127; PET, n = 121), compared with the placebo group (sMRI, n = 66; PET, n = 62). Voxels showing this interaction are shown at the uncorrected threshold P < 0.05 (magenta color) on a population-specific cortical surface. The left and right hemispheres are shown in the top and bottom rows, respectively. Brain regions showing interactions inconsistent with the hypothesis are shown in Figure 7 in the Supplementary Data.
b. Total number of voxels in pre-defined vulnerable AD brain regions (total area of pie charts) showing either hypothesis-consistent interaction (magent color) or hypothesis-inconsistent interaction (yellow color) in each of the imaging modalities (cMRI, left panel; FDG PET, right panel) at increasingly liberal unadjusted P thresholds < 0.01 and P < 0.05. Monte Carlo simulations showed that the ratios of voxels showing effects consistent with the hypothesis versus those not consistent with the hypothesis were significantly higher than those observed from randomly generated data for both cMRI and PET ( P < 0.001 for each method; two-tailed test).

LM11A-31 effectively reduced the increase in Aβ42 and Aβ40 in CSF compared with the placebo group. The drug also showed a decrease in the median annual percentage change in the presynaptic protein biomarker SNAP25 and a decrease in the postsynaptic biomarker NG, indicating a slowdown in the loss of presynaptic and postsynaptic connections. LM11A-31 also reduced YKL40 growth, resulting in decreased MMSE scores and increased ADAS-Cog-13 scores. The drug also reduced gray matter loss in the frontal lobe and posterior parietal cortex and decreased glucose metabolism in areas such as the entorhinal cortex, temporal cortex, hippocampus, insular cortex, and prefrontal cortex.

Conclusion

The study concluded that modulation of p75NTR by LM11A-31 is suitable for larger clinical trials. LM11A-31 met the primary safety criterion and was well tolerated by patients with mild to severe forms of asthma. The results indicate the need for further studies with longer treatment durations to evaluate the feasibility of using small molecules to regulate p75NTR as a disease-modifying therapy in AD. The study found that LM11A-31 significantly affected several biomarkers, including Aβ40, Aβ42, SNAP25, NG, and YKL40, indicating attenuation of pathological development. Future studies may evaluate additional indicators of glial health.