This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-R1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heighten

• Status: NOT_YET_RECRUITING
• Trial end date: 2028-01-01

Summary

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to muscle weakness, respiratory decline, and eventual mortality. A growing body of translational and clinical evidence implicates neuroinflammation, reactive astrocytosis, and maladaptive TGF- signaling as central contributors to disease progression. Elevated levels of Gremlin-2 (GREM2) have been identified as a marker of dysregulated TGF--linked astrocytic activity and fibrotic gene programs in some ALS patients, and preclinical data suggest that attenuating these pathways may mitigate glial toxicity and improve neuronal survival.

Galunisertib, a selective ATP-competitive TGF- receptor type I (TGF-R1/ALK5) inhibitor, has been developed to block SMAD2/3 phosphorylation and TGF--mediated transcriptional programs. Meanwhile, nerandomilast, a selective PDE4B inhibitor, elevates intracellular cAMP in immune and glial cells, shifting pro-inflammatory signaling toward resolution and antagonizing secondary fibrotic and inflammatory cascades. Preclinical models show that PDE4 inhibition and TGF- pathway blockade concurrently reduce maladaptive glial phenotypes and fibrotic mediators.

This study investigates the combination of galunisertib + nerandomilast in ALS patients with elevated GREM2, hypothesizing that dual targeting of TGF--mediated astrocytic reactivity and PDE4B-regulated inflammatory signaling will translate into slowing of disease progression and favorable pharmacodynamic effects on central biomarkers of neuroinflammation and neurodegeneration.

• Phase: PHASE2

Details

• Lead Sponsor: Gipfel Life Sciences GmbH
• Treatments: LY-2157299