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

Autor: Perrin, Steven, Ladha, Shafeeq, Maragakis, Nicholas, Rivner, Michael H., Katz, Jonathan, Genge, Angela, Olney, Nicholas, Lange, Dale, Heitzman, Daragh, Bodkin, Cynthia, Jawdat, Omar, Goyal, Namita A., Bornstein, Jeffrey D., Mak, Carmen, Appel, Stanley H., Paganoni, Sabrina
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Zdroj: PLoS Medicine; 10/31/2024, Vol. 21 Issue 10, p1-18, 18p
Abstrakt: 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. Steven Perrin and colleagues report on the safety and tolerability of different doses of the novel drug tegoprubart in patients with Amyotrophic Lateral Sclerosis. Author summary: Why was this study done?: One of the critical pathways controlling activation of T cells and B cells, cells which are pivotal in inducing inflammation in the body, involves a protein called CD40L and its receptor, CD40. Uncontrolled activation of CD40L/CD40 results in autoimmune disorders and the biological processes associated with organ transplant rejection. The activation of CD40L/CD40 has also been shown to occur in individuals with amyotrophic lateral sclerosis (ALS) as well as in animal models of ALS. Indeed, modulation of CD40L signaling ameliorates disease progression, improves survival, and decreases peripheral and neuroinflammation in rodent models of ALS. This study aimed to assess the safety and impact of an anti CD40L antibody, tegoprubart, on pro-inflammatory biomarkers in patients with ALS. What did the researchers find?: We designed an open label, dose escalating study of tegoprubart in adults with ALS to assess the safety of tegoprubart at multiple doses and to study the effects of increasing doses of tegoprubart on inflammatory biomarkers in the blood. In this dose escalating study, tegoprubart appeared safe and well tolerated in 54 participants with ALS at all 4 doses studied. The amount of tegoprubart in blood increased with increasing dose. The study demonstrated target engagement with a dose-dependent decrease in the levels of CD40L and CXCL13. The study demonstrated a dose-dependent decrease in pro-inflammatory biomarkers after a single infusion of tegoprubart. What do the findings mean?: This is the first clinical study of an anti CD40L antibody in ALS patients. The results suggest the inhibition of CD40L is safe and well tolerated and results in a dose-dependent reduction in a broad spectrum of T cell and myeloid associated pro-inflammatory signaling pathways in adults with ALS. These data support the further exploration of tegoprubart in a randomized, standard of care-controlled trial as a potential treatment for patients with ALS. There are 2 major limitations with the study: it is an open label study with no standard of care arm and the study was not powered to detect changes in clinical outcomes; the study was 12 weeks in duration which is not of sufficient duration to assess changes in clinical outcomes. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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