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-β signaling as central contributors to disease progression. Elevated levels of Gremlin-2 (GREM2) have been identified as a marker of dysregulated TGF-β-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-β receptor type I (TGF-βR1/ALK5) inhibitor, has been developed to block SMAD2/3 phosphorylation and TGF-β-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-β 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-β-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.
18 to 80 years, inclusive, at the time of informed consent.
Diagnosis of amyotrophic lateral sclerosis according to revised El Escorial criteria or equivalent, confirmed by a qualified neurologist.
CSF GREM2 above a pre-specified threshold OR
Plasma GREM2 above a pre-specified threshold with supportive evidence of astrocytic or TGF-β pathway activation (e.g., elevated GFAP or TGF-β-responsive biomarker).
Diagnosis of primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), or other non-ALS motor neuron disorders.
Requirement for invasive mechanical ventilation at screening or anticipated need within the immediate study period.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN) at screening.
Known cirrhosis or active chronic liver disease.
Parallel
Galunisertib + Nerandomilast Combination
DrugGalunisertib + Nerandomilast Combination
Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels
Pharmacodynamic Biomarkers - Change from Baseline in GREM2 and TGF-β Pathway Marker Levels (CSF or plasma; Time Frame: Baseline to 24 Weeks). Definition: GREM2 (Gremlin-2) concentration in cerebrospinal fluid or plasma will be measured at baseline and 24 weeks. GREM2 is a TGF-β-inducible protein  used to stratify patients (GREM2-positive) and serves as a proxy for TGF-β pathway activity. In addition, downstream TGF-β signaling biomarkers will be assessed over the same period, including phosphorylated SMAD2/3 (pSMAD2/3) in peripheral blood cells and plasminogen activator inhibitor-1 (PAI-1, SERPINE1) in plasma. These are direct readouts of TGF-β receptor activity  and are strongly upregulated by TGF-β signaling . Glial/neuroinflammatory markers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in CSF or blood will also be measured, as they indicate astrocyte activation and neuroaxonal injury in ALS . Analysis: Changes from baseline in GREM2 and the
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