Safety and activity of anti‐CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol

Abstract

Introduction/Aims IC14 (atibuclimab) is a monoclonal anti‐CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long‐term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints. Methods Participants received intravenous IC14 every 2 weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T‐regulatory functional assays were performed in a subset of participants. Results Seventeen participants received IC14 for up to 103 weeks (average, 30.1 weeks; range, 1 to 103 weeks). Treatment‐emergent adverse events (TEAEs) were uncommon, mild, and self‐limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10 days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non‐neutralizing. Discussion Administration of IC14 in ALS was safe and well‐tolerated in this intermediate‐size EAP. Measuring RO guided dosing frequency. Additional placebo‐controlled trials are required to determine the efficacy of IC14 in ALS.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS)

“…Biofluid bio‐samples for biomarker analysis were obtained in select EAPs (frequency and process varied based on the IP's mechanism of action). While some analyses are still ongoing, results from two protocols have been recently reported 4,5 …”

“…These data can provide valuable pharmacokinetic and pharmacodynamic information to supplement clinical development programs as recently reported. 4,5 As described above, contemporary EAPs funded through the ACT for ALS are expected to produce extensive datasets that can be integrated with those generated by formal clinical trials. These innovative study designs are an exciting new frontier in ALS research.…”

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis

“…For instance, we previously reported biomarker data from our single-center EAP experience with RT001 and a monoclonal anti-CD14 antibody (IC14). 14,15 The RT001 EAP helped to guide dosing of a randomized, double-blind, placebo-controlled Phase 2 ALS trial where the safety and efficacy of RT001 were formally tested (NCT04762589, https://clinicaltrials.gov/ct2/show/NCT04762589). Furthermore, our experience suggests that EAPs can be readily conducted in parallel to active trials without harming trial enrollment rates.…”

A novel patient-derived cellular platform for validating microglia-targeted therapeutics for Alzheimer’s disease

“…Minocycline, a well-known anti-inflammatory drug, has shown effectiveness in rodent and immortalised microglial models but has failed in clinical testing for AD patients (14)(15)(16). IC14, an anti-CD14 monoclonal antibody, is currently under clinical investigation for treating inflammation related to SARS-Cov-2 and amyotrophic lateral sclerosis (ALS) and has potential for repurposing in AD patients (17)(18)(19). We have identified differences in MDMi responses to both drugs, which could aid in predicting the efficacy of new compounds before clinical evaluation.…”