LB: IGFBP7 as a Nexus Biomarker Identifying a Coordinated Treatment Response Phenotype in ALS: Post-Hoc Exploratory Analysis from Regimen C of the HEALEY

Topic:

Other

Poster Number: 469 LBM

Author(s):

Marjan Sepassi, PharmD, Clene Nanomedicine Inc., Richard Bedlack, MD, Duke University, Jinsy Andrews, MD, NYU Langone Health, Robert Bowser, PhD, Barrow Neurological Institute, Bernard Caparrelli, NYU Langone Health, Austin Rynders, RN, Clene Nanomedicine, Jacob Evan, PA-C, Clene Nanomedicine, Jeremy Evan, PA-C, Clene Nanomedicine, Alan Hartford, PhD, Clene Nanomedicine, Benjamin Greenberg, MD, UT Southwestern Medical Center, Michael Hotchkin, Clene Nanomedicine

OBJECTIVE: Investigate biomarker responses associated with survival in CNM-Au8 treated ALS patients linked to a treatment response phenotype.

BACKGROUND: CNM-Au8 is a catalytic nanomedicine targeting cellular metabolic support. In the HEALEY ALS Platform Trial Regimen C, CNM-Au8 30mg did not meet the primary endpoint (ALSFRS-R) but did demonstrate a nominally significant survival benefit versus placebo during the 24-week double-blind period. Based on recent reports, we hypothesized that IGFBP7 decline identifies a coordinated biomarker response predictive of improved survival.

DESIGN/METHODS: We examined 56 CNM-Au8 30mg participants with NULISA CNS Disease Panel biomarker data (all evaluable with plasma samples). Pairwise correlations were compared between responders and non-responders. Cox proportional hazards models assessed survival versus concurrently randomized HEALEY platform controls (n=162), adjusting for prespecified baseline covariates. Survival was assessed at median treatment discontinuation (Day 487) and through cessation of the open-label extension (Day 878); both intervals representing attenuated effects due to treatment discontinuation.

RESULTS: Thirty-six patients (64%) met IGFBP7 responder criteria (AUC W0-24 decline); 13 biomarkers showed significant correlation with IGFBP7 and concordant survival associations (n=14), including NfL and pNfH (range, r=0.4-0.8, p<0.01). Non-responder (n=20) network correlation network collapsed to near-zero connectivity. IGFBP7 decline was associated with improved survival at Day 487 (HR=0.17, 95% CI: 0.04-0.70, p=0.014; 83% risk reduction) and Day 878 (HR=0.49, 95% CI: 0.27-0.89, p=0.019; 51% risk reduction). Non-responders demonstrated no survival benefit versus controls, confirming IGFBP7 specificity. Consistent survival associations were also observed for the multi-biomarker AUC W0-24 decline (>8 of the 14), Day 487 HR=0.24, p=0.017; Day 878 HR=0.47, p=0.019).

CONCLUSIONS: IGFBP7 functions as a nexus biomarker whose coordinated decline with 13 other neurodegeneration-related markers identifies an ALS treatment response phenotype. The striking correlation collapse in non-responders suggests IGFBP7 connectivity may distinguish genuine biological responders from non-responders to CNM-Au8 to inform enrichment strategies and therapeutic response in future ALS trials.