Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial

Abstract

Background: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).

Methods and findings: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.

Conclusions: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.

Trial registration: Clintrials.gov ID:NCT04322149.

Fig 1. Participant disposition.

Open label dose escalating study of AT-1501 in patients with ALS. Percentages reflect completed their last visit at week 12 and their post follow-up visit at week 15.

Fig 2. Plasma concentrations of AT-1501 over time in study AT-1501-A201 (Pharmacokinetic Population).

Circulating concentrations of AT-1501 for each participant in each cohort: 1 mg/kg cohort (n = 9) gold; 2 mg/kg cohort (n = 9) green; 4 mg/kg cohort (n = 18) blue; 8 mg/kg cohort (n = 18) pink were determined by ELISA at the indicated time points. AT-1501 is the generic name for tegoprubart. AT-1501-A201 is the clinical study name for this Phase 2 study of tegoprubart in patients with ALS.

Fig 3. Biomarkers of target engagement.

(A, B) The axis is dose in mg/kg. The Y axis is the percent mean reductions in protein biomarkers from baseline to Day 71. Error bars are standard error of the mean for participants in each cohort respectively.

Fig 4. Mean changes (+/− SEM) in pro-inflammatory proteins by tegoprubart dose groups.

Forest plots for dose-dependent reduction of pro-inflammatory biomarkers. Forest plots graph the percent mean reductions in protein biomarkers from baseline to Day 71 on the X axis. Error bars are standard error of the mean for participants in each cohort, respectively.