Background & Aims

LAT8881, a member of a family of peptide motifs with analgesic properties in rodent models of neuropathic pain, acts via the LanC-like (LanCL) protein family, a novel therapeutic target for neuropathic pain.(1) We previously reported on a placebo-controlled Phase 1b clinical trial where a single IV dose of LAT8881 safely provided analgesia following a straight-leg raise provocation in subjects with chronic moderate-to-severe lumbar radicular pain (LRP).(2) In this follow-on analysis of plasma samples taken pre- and post-dosing during the study, we compared the proteomic profile in the healthy volunteers and the LRP subjects, with the aim of identifying possible pharmacodynamic (PD) biomarkers of pain and of LAT8881 activity.

Methods

This was a placebo-controlled randomized double-blind cross-over safety and efficacy study in 17 patients with moderate-to-severe chronic lumbar radicular pain.(3) Placebo or LAT8881 was given intravenously over 10 minutes on two consecutive days with any impact on pain scores at rest and after a straight-leg raise provocation monitored during the 6 hours post-dose. Exploratory outcome measures included investigation of a pharmacodynamic assay and/or biomarkers of LAT8881 activity.(2,3)

For the PD investigations, plasma samples at pre-dose, 1 and 6 hours post-dose were collected from 3 healthy volunteers and the 17 LRP subjects treated with placebo and with LAT8881. The plasma samples were assayed using the SomaLogic SomaScan® Custom Panel 1500 and subsequent normalized expression data were imported into R using the SomaDataIO package.(4) Differential expression analyses were performed using limma, comparing subjects to controls and examining changes over time with treatment.

Results

LAT8881 was more effective than Placebo in reducing provoked pain, particularly during the 1-2 hours post-dose. The LAT8881 half-life was less than 30 minutes, with a mean AUC0-t of 39.78 ng/ml*h and 89.4 ng/ml*h, and tmax of 8 and 10 minutes, for the parent and active metabolite, respectively.

In the PD plasma sample analyses:
-The levels of insulin were higher at 6 hours post-dosing, which correlates with subjects fasting overnight prior to dosing
-Comparing the healthy volunteer and LRP samples, some variation in protein levels between healthy volunteers and LRP samples were observed, such as levels of C-reactive protein, a marker of inflammation, being significantly higher in LRP
-Comparison of LRP plasma samples taken on the LAT8881 versus the Placebo treatment day revealed differentially expressed differentially expressed proteins reaching statistical significance at the 1 hour timepoint: HEPACAM, FXRD1, Hexosaminidase A, FLIP, WN10A, E2AK4, TXD15, Neprilysin, and MAPIP.

Conclusions

Having demonstrated clinical “proof-of-concept” of LAT8881 as a novel first-in-class therapeutic for the treatment of neuropathic pain, proteomic analysis of plasma samples taken from the study subjects has identified a number of differentially expressed proteins in LAT8881 treated subjects, particularly at 1 hour post-dosing. These results could provide the foundation for a pharmacodynamic assay of LanCL target engagement, which would aid screening of potential LAT therapeutics and support investigations into optimal dosing of these therapeutics in future clinical trials.

We also observed differences between healthy volunteers and LRP subjects in expression of a number of proteins, including CRP ; a larger sample size (only samples from 3 healthy volunteers were included in this analysis) may be more informative.

References

1. Wei et al, 2022, PWD221, IASP World Pain Congress 2022
2. Walsh et al, 2023, Poster FR39, NeuPSIG Conference 2023
3. ClinicalTrials.gov Identifier: NCT05298306
4. https://somalogic.com/

Presenting Author

Stuart Mudge

Poster Authors

Stuart Mudge

BSc(Hons) PhD

Lateral Pharma Pty Ltd

Lead Author

E-mail

Topics

  • Treatment/Management: Pharmacology: Non-opioid